142 results on '"Joanne J. Bronson"'
Search Results
2. Discovery of (S)-1-((2′,6-Bis(difluoromethyl)-[2,4′-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine (BMS-986176/LX-9211): A Highly Selective, CNS Penetrable, and Orally Active Adaptor Protein-2 Associated Kinase 1 Inhibitor in Clinical Trials for the Treatment of Neuropathic Pain
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Guanglin Luo, Ling Chen, Walter A. Kostich, Brian Hamman, Jason Allen, Amy Easton, Clotilde Bourin, Michael Gulianello, Jonathan Lippy, Susheel Nara, Tarun Kumar Maishal, Kamalraj Thiyagarajan, Prasadrao Jalagam, Sreenivasulu Naidu Pattipati, Kumaran Dandapani, Manoj Dokania, Pradeep Vattikundala, Vivek Sharma, Saravanan Elavazhagan, Manoj Kumar Verma, Manish Lal Das, Santosh Wagh, Anand Balakrishnan, Benjamin M. Johnson, Kenneth S. Santone, George Thalody, Rex Denton, Hariharan Saminathan, Vinay K. Holenarsipur, Anoop Kumar, Abhijith Rao, Siva Prasad Putlur, Sarat Kumar Sarvasiddhi, Ganesh Shankar, Justin V. Louis, Manjunath Ramarao, Charles M. Conway, Yu-Wen Li, Rick Pieschl, Yuan Tian, Yang Hong, Jonathan Ditta, Arvind Mathur, Jianqing Li, Daniel Smith, Joseph Pawluczyk, Dawn Sun, Shiuhang Yip, Dauh-Rurng Wu, Muthalagu Vetrichelvan, Anuradha Gupta, Alan Wilson, Suma Gopinathan, Suman Wason, Linda Bristow, Charles F. Albright, Joanne J. Bronson, John E. Macor, and Carolyn D. Dzierba
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Drug Discovery ,Molecular Medicine - Published
- 2022
3. Bicyclic Heterocyclic Replacement of an Aryl Amide Leading to Potent and Kinase-Selective Adaptor Protein 2-Associated Kinase 1 Inhibitors
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Richard A. Hartz, Vijay T. Ahuja, Susheel J. Nara, C. M. Vijaya Kumar, Raju K. V. L. P. Manepalli, Sarat Kumar Sarvasiddhi, Swarnamba Honkhambe, Vidya Patankar, Bireshwar Dasgupta, Ramkumar Rajamani, Jodi K. Muckelbauer, Daniel M. Camac, Kaushik Ghosh, Matthew Pokross, Susan E. Kiefer, Jeffrey M. Brown, Lisa Hunihan, Michael Gulianello, Martin Lewis, Jonathan S. Lippy, Neha Surti, Brian D. Hamman, Jason Allen, Walter A. Kostich, Joanne J. Bronson, John E. Macor, and Carolyn D. Dzierba
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Structure-Activity Relationship ,Drug Discovery ,Quinazolines ,Quinolines ,Animals ,Neuralgia ,Molecular Medicine ,Amides ,Protein Kinase Inhibitors - Abstract
Adaptor protein 2-associated kinase 1 (AAK1) is a serine/threonine kinase that was identified as a therapeutic target for the potential treatment of neuropathic pain. Inhibition of AAK1 in the central nervous system, particularly within the spinal cord, was found to be the relevant site for achieving an antinociceptive effect. We previously reported that compound
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- 2022
4. Discovery of (
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Guanglin, Luo, Ling, Chen, Walter A, Kostich, Brian, Hamman, Jason, Allen, Amy, Easton, Clotilde, Bourin, Michael, Gulianello, Jonathan, Lippy, Susheel, Nara, Tarun Kumar, Maishal, Kamalraj, Thiyagarajan, Prasadrao, Jalagam, Sreenivasulu Naidu, Pattipati, Kumaran, Dandapani, Manoj, Dokania, Pradeep, Vattikundala, Vivek, Sharma, Saravanan, Elavazhagan, Manoj Kumar, Verma, Manish Lal, Das, Santosh, Wagh, Anand, Balakrishnan, Benjamin M, Johnson, Kenneth S, Santone, George, Thalody, Rex, Denton, Hariharan, Saminathan, Vinay K, Holenarsipur, Anoop, Kumar, Abhijith, Rao, Siva Prasad, Putlur, Sarat Kumar, Sarvasiddhi, Ganesh, Shankar, Justin V, Louis, Manjunath, Ramarao, Charles M, Conway, Yu-Wen, Li, Rick, Pieschl, Yuan, Tian, Yang, Hong, Jonathan, Ditta, Arvind, Mathur, Jianqing, Li, Daniel, Smith, Joseph, Pawluczyk, Dawn, Sun, Shiuhang, Yip, Dauh-Rurng, Wu, Muthalagu, Vetrichelvan, Anuradha, Gupta, Alan, Wilson, Suma, Gopinathan, Suman, Wason, Linda, Bristow, Charles F, Albright, Joanne J, Bronson, John E, Macor, and Carolyn D, Dzierba
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Mice ,Spinal Cord ,Animals ,Brain ,Neuralgia ,Amines ,Protein Kinase Inhibitors ,Rats - Abstract
Recent mouse knockout studies identified adapter protein-2 associated kinase 1 (AAK1) as a viable target for treating neuropathic pain. Potent small-molecule inhibitors of AAK1 have been identified and show efficacy in various rodent pain models. (
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- 2022
5. Discovery, Structure-Activity Relationships, and In Vivo Evaluation of Novel Aryl Amides as Brain Penetrant Adaptor Protein 2-Associated Kinase 1 (AAK1) Inhibitors for the Treatment of Neuropathic Pain
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Jodi K. Muckelbauer, Ramkumar Rajamani, Jeffrey M. Brown, C M Vijaya Kumar, Kumaran Dandapani, Jonathan Lippy, Saravanan Elavazhagan, Vijay T. Ahuja, John E. Macor, Carolyn Diane Dzierba, Brian D. Hamman, Walter Kostich, Michael Gulianello, Manoj Dokania, Susan E. Kiefer, Susheel J. Nara, Joanne J. Bronson, Amy Easton, Richard A. Hartz, Linda J. Bristow, Martin A. Lewis, Jason Allen, Sreenivasulu N Pattipati, Neha Surti, Lisa Hunihan, and Daniel M. Camac
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Male ,Phenotypic screening ,Pharmacology ,Protein Serine-Threonine Kinases ,chemistry.chemical_compound ,Mice ,Structure-Activity Relationship ,In vivo ,Drug Discovery ,medicine ,Animals ,Humans ,Dose-Response Relationship, Drug ,Molecular Structure ,Kinase ,Chemistry ,Anti-Inflammatory Agents, Non-Steroidal ,Chronic pain ,AAK1 ,Signal transducing adaptor protein ,Brain ,medicine.disease ,Amides ,Mice, Inbred C57BL ,HEK293 Cells ,Neuropathic pain ,Microsomes, Liver ,Molecular Medicine ,Neuralgia ,Caco-2 Cells ,Penetrant (biochemical) ,Protein Kinases - Abstract
Effective treatment of chronic pain, in particular neuropathic pain, without the side effects that often accompany currently available treatment options is an area of significant unmet medical need. A phenotypic screen of mouse gene knockouts led to the discovery that adaptor protein 2-associated kinase 1 (AAK1) is a potential therapeutic target for neuropathic pain. The synthesis and optimization of structure-activity relationships of a series of aryl amide-based AAK1 inhibitors led to the identification of 59, a brain penetrant, AAK1-selective inhibitor that proved to be a valuable tool compound. Compound 59 was evaluated in mice for the inhibition of μ2 phosphorylation. Studies conducted with 59 in pain models demonstrated that this compound was efficacious in the phase II formalin model for persistent pain and the chronic-constriction-injury-induced model for neuropathic pain in rats. These results suggest that AAK1 inhibition is a promising approach for the treatment of neuropathic pain.
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- 2021
6. The discovery of VU0652957 (VU2957, Valiglurax): SAR and DMPK challenges en route to an mGlu4 PAM development candidate
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Corey R. Hopkins, Anna L. Blobaum, Joshua M. Wieting, Ryan Westphal, Rory A. Capstick, Alison R. Gregro, Julie E. Engers, Aspen Chun, P. Jeffrey Conn, Jason M. Guernon, Carrie K. Jones, Alice L. Rodriguez, Darren W. Engers, Joseph D. Panarese, Craig W. Lindsley, Wu Yong Jin, Joanne J. Bronson, John E. Macor, Andrew S. Felts, Kyle A. Emmitte, Colleen M. Niswender, Aaron M. Bender, and Matthew Soars
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Allosteric modulator ,010405 organic chemistry ,Chemistry ,Organic Chemistry ,Clinical Biochemistry ,Allosteric regulation ,Pharmaceutical Science ,Computational biology ,01 natural sciences ,Biochemistry ,0104 chemical sciences ,Cns penetration ,010404 medicinal & biomolecular chemistry ,Metabotropic glutamate receptor ,Drug Discovery ,Molecular Medicine ,skin and connective tissue diseases ,Molecular Biology - Abstract
This letter describes the first account of the chemical optimization (SAR and DMPK profiling) of a new series of mGlu4 positive allosteric modulators (PAMs), leading to the identification of VU0652957 (VU2957, Valiglurax), a compound profiled as a preclinical development candidate. Here, we detail the challenges faced in allosteric modulator programs (e.g., steep SAR, as well as subtle structural changes affecting overall physiochemical/DMPK properties and CNS penetration).
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- 2019
7. Discovery of VU2957 (Valiglurax): An mGlu4 Positive Allosteric Modulator Evaluated as a Preclinical Candidate for the Treatment of Parkinson’s Disease
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Michael J. Kates, Arlindo L. Castelhano, Carrie K. Jones, Colleen M. Niswender, Andrew S. Felts, Anna L. Blobaum, Matthew T. Loch, Kyle A. Emmitte, Aspen Chun, John E. Macor, Joanne J. Bronson, Darren W. Engers, Alice L. Rodriguez, Julie L. Engers, Joseph D. Panarese, Craig W. Lindsley, Michael A. Nader, Wu Yong Jin, P. Jeffrey Conn, and Corey R. Hopkins
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Allosteric modulator ,Parkinson's disease ,010405 organic chemistry ,business.industry ,Organic Chemistry ,Pharmacology ,medicine.disease ,01 natural sciences ,Biochemistry ,0104 chemical sciences ,Toxicology studies ,010404 medicinal & biomolecular chemistry ,chemistry.chemical_compound ,chemistry ,In vivo ,Drug Discovery ,medicine ,business ,Penetrant (biochemical) - Abstract
[Image: see text] Herein, we report the discovery of a novel potent, selective, CNS penetrant, and orally bioavailable mGlu(4) PAM, VU0652957 (VU2957, Valiglurax). VU2957 possessed attractive in vitro and in vivo pharmacological and DMPK properties across species. To advance toward the clinic, a spray-dried dispersion (SDD) formulation of VU2957 was developed to support IND-enabling toxicology studies. Based on its overall profile, VU2957 was evaluated as a preclinical development candidate for the treatment of Parkinson’s disease.
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- 2018
8. Discovery and characterization of N-(1,3-dialkyl-1H-indazol-6-yl)-1H-pyrazolo[4,3-b]pyridin-3-amine scaffold as mGlu4 positive allosteric modulators that mitigate CYP1A2 induction liability
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John E. Macor, Darren W. Engers, Julie L. Engers, Colleen M. Niswender, P. Jeffrey Conn, Rocio Zamorano, Alice L. Rodriguez, Joanne J. Bronson, Sean R. Bollinger, Anna L. Blobaum, Joseph D. Panarese, Craig W. Lindsley, Alison R. Gregro, Corey R. Hopkins, Wu Yong Jin, and Megan M. Breiner
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0301 basic medicine ,Scaffold ,Chemistry ,Stereochemistry ,Organic Chemistry ,Clinical Biochemistry ,Allosteric regulation ,CYP1A2 ,Pharmaceutical Science ,Biochemistry ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,In vivo ,Drug Discovery ,Molecular Medicine ,Potency ,Amine gas treating ,Selectivity ,Molecular Biology ,030217 neurology & neurosurgery - Abstract
Previous reports from our laboratory disclosed the structure and activity of a novel 1H-pyrazolo[4,3-b]pyridine-3-amine scaffold (VU8506) which showed excellent potency, selectivity and in vivo efficacy in preclinical rodent models of Parkinson’s disease. Unfortunately, this compound suffered from significant CYP1A2 induction as measured through upstream AhR activation (125-fold) and thus was precluded from further advancement in chronic studies. Herein, we report a new scaffold developed recently which was systematically studied in order to mitigate the CYP1A2 liabilities presented in the earlier scaffolds. We have identified a novel structure that maintains the potency and selectivity of other mGlu4 PAMs, leading to 9i (hmGlu4 EC50 = 43 nM; AhR activation = 2.3-fold).
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- 2018
9. Discovery of non-zwitterionic aryl sulfonamides as Nav1.7 inhibitors with efficacy in preclinical behavioral models and translational measures of nociceptive neuron activation
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Kathleen W. Mosure, Michele Matchett, Ronald J. Knox, Richard E. Olson, Joanne J. Bronson, Nicholas A. Meanwell, Matthew G. Soars, Linda J. Bristow, Ramkumar Rajamani, James Herrington, Amy Easton, Digavalli V. Sivarao, Dawn D. Parker, Rick L. Pieschl, Ping Chen, Guanglin Luo, Omar S. Barnaby, Lorin A. Thompson, Yong-Jin Wu, Andrea McClure, Jason M. Guernon, Amy Newton, Alicia Ng, Clotilde Bourin, and Carolyn Diane Dzierba
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0301 basic medicine ,chemistry.chemical_classification ,Membrane permeability ,Bicyclic molecule ,Aryl ,Organic Chemistry ,Clinical Biochemistry ,Pharmaceutical Science ,Pharmacology ,Biochemistry ,Sulfonamide ,03 medical and health sciences ,chemistry.chemical_compound ,030104 developmental biology ,medicine.anatomical_structure ,Nociception ,chemistry ,Drug Discovery ,NAV1 ,medicine ,Molecular Medicine ,Moiety ,Neuron ,Molecular Biology - Abstract
Since zwitterionic benzenesulfonamide Nav1.7 inhibitors suffer from poor membrane permeability, we sought to eliminate this characteristic by replacing the basic moiety with non-basic bicyclic acetals and monocyclic ethers. These efforts led to the discovery of the non-zwitterionic aryl sulfonamide 49 as a selective Nav1.7 inhibitor with improved membrane permeability. Despite its moderate cellular activity, 49 exhibited robust efficacy in mouse models of neuropathic and inflammatory pain and modulated translational electromyogram measures associated with activation of nociceptive neurons.
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- 2017
10. Preclinical Characterization of (R)-3-((3S,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one (BMS-986169), a Novel, Intravenous, Glutamate N-Methyl-d-Aspartate 2B Receptor Negative Allosteric Modulator with Potential in Major Depressive Disorder
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Mahesh Paschapur, Jeffrey M. Brown, Tanmaya Bastia, Lawrence R. Marcin, Jayakumar Sankara Warrier, Srinivasan Thangathirupathy, Joanne J. Bronson, Raja Reddy Kallem, Huiping Zhang, Jyoti Gulia, Alda Fernandes, Digavalli V. Sivarao, Deborah Keavy, Amy Newton, Jianqing Li, Pattipati S. Naidu, Kuchibhotla Vijaya Kumar, James Kempson, Michael R. Weed, Rick L. Pieschl, Mark Bookbinder, Charlie F. Albright, Kimberly Newberry, Yu-Wen Li, Dalton King, Manjunath Ramarao, Jean Simmermacher, Linda J. Bristow, Meenakshee Sinha, Eric Shields, Lorin A. Thompson, John E. Macor, Charulatha Sanmathi, Imadul Islam, B.N. Srikumar, Richard E. Olson, John D. Graef, Arvind Mathur, Narasimharaju Kalidindi, Joseph Polino, Michael Sinz, Thaddeus F. Molski, Jayant Aher, and Reeba K. Vikramadithyan
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0301 basic medicine ,Pharmacology ,Allosteric modulator ,Chemistry ,digestive, oral, and skin physiology ,Allosteric regulation ,Glutamate receptor ,Long-term potentiation ,Prodrug ,stomatognathic diseases ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,In vivo ,Molecular Medicine ,Receptor ,030217 neurology & neurosurgery ,Ex vivo - Abstract
(R)-3-((3S,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one (BMS-986169) and the phosphate prodrug 4-((3S,4S)-3-fluoro-1-((R)-1-(4-methylbenzyl)-2-oxopyrrolidin-3-yl)piperidin-4-yl)phenyl dihydrogen phosphate (BMS-986163) were identified from a drug discovery effort focused on the development of novel, intravenous glutamate N-methyl-d-aspartate 2B receptor (GluN2B) negative allosteric modulators (NAMs) for treatment-resistant depression (TRD). BMS-986169 showed high binding affinity for the GluN2B subunit allosteric modulatory site (Ki = 4.03-6.3 nM) and selectively inhibited GluN2B receptor function in Xenopus oocytes expressing human N-methyl-d-aspartate receptor subtypes (IC50 = 24.1 nM). BMS-986169 weakly inhibited human ether-a-go-go-related gene channel activity (IC50 = 28.4 μM) and had negligible activity in an assay panel containing 40 additional pharmacological targets. Intravenous administration of BMS-986169 or BMS-986163 dose-dependently increased GluN2B receptor occupancy and inhibited in vivo [3H](+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine ([3H]MK-801) binding, confirming target engagement and effective cleavage of the prodrug. BMS-986169 reduced immobility in the mouse forced swim test, an effect similar to intravenous ketamine treatment. Decreased novelty suppressed feeding latency, and increased ex vivo hippocampal long-term potentiation was also seen 24 hours after acute BMS-986163 or BMS-986169 administration. BMS-986169 did not produce ketamine-like hyperlocomotion or abnormal behaviors in mice or cynomolgus monkeys but did produce a transient working memory impairment in monkeys that was closely related to plasma exposure. Finally, BMS-986163 produced robust changes in the quantitative electroencephalogram power band distribution, a translational measure that can be used to assess pharmacodynamic activity in healthy humans. Due to the poor aqueous solubility of BMS-986169, BMS-986163 was selected as the lead GluN2B NAM candidate for further evaluation as a novel intravenous agent for TRD.
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- 2017
11. [ 3 H]BMT-046091 a potent and selective radioligand to determine AAK1 distribution and target engagement
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Justin Vijay Louis, Kumaran Dandapani, Susheel J. Nara, Yang Hong, Yung Tian, Sarat Kumar Sarvasiddhi, Yifeng Lu, Carolyn Diane Dzierba, Walter Kostich, Yu-Wen Li, Rick L. Pieschl, Sreenivasulu Naidu, Charlie F. Albright, Joanne J. Bronson, John E. Macor, and Reeba K. Vikramadithyan
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0301 basic medicine ,Pharmacology ,Kinase ,Central nervous system ,Biology ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,030104 developmental biology ,0302 clinical medicine ,medicine.anatomical_structure ,Nociception ,Knockout mouse ,Radioligand ,medicine ,Phosphorylation ,Binding site ,Receptor ,Neuroscience ,030217 neurology & neurosurgery - Abstract
Adaptor-associated kinase 1 (AAK1), a member of the Ark1/Prk1 family of serine/threonine kinases, plays a role in modulating clatherin coated endocytosis of specific surface receptors. We have demonstrated that AAK1 inhibitors are efficacious in rodent models of neuropathic pain (Kostich et al., 2016). Here we have characterized the binding properties and distribution pattern of the tritiated AAK1 radioligand, [3H]BMT-046091, in rodents and cynomolgus monkeys, and used the radioligand to measure the brain target occupancy following systemic administration of AAK1 inhibitors. We have found that [3H]BMT-046091 is potent and selective AAK1 inhibitor. It inhibits AAK1 phosphorylation of a peptide derived from a physiologic substrate, the μ2 subunit of the adaptor protein complex, with an IC50 value of 2.8 nM, and is inactive at >5 μM in a panel of functional or binding assays for receptors, transporters and enzymes. [3H]BMT-046091 binding in the brain is absent in the AAK1 knockout mouse, and is displaceable with a high concentration of AAK1 inhibitors in wild type mice. Specific [3H]BMT-046091 binding is widespread in the brain and spinal cord with the highest density in the cortex, hippocampus, amygdala, striatum and thalamus. In the spinal cord, [3H]BMT-046091 binding appears enriched in the dorsal horn superficial layers. Oral administration of LP-935509, an AAK1 inhibitor, results in a dose-dependent occupation of AAK1 binding sites in the brain and spinal cord. The increase in AAK1 binding site occupancy by LP-935509 correlates with the decrease in antinociceptive responses in the rat chronic constriction injury model of neuropathic pain.
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- 2017
12. Synthesis and evaluation of prodrugs of corticotropin-releasing factor-1 (CRF 1 ) receptor antagonist BMS-665053 leading to improved oral bioavailability
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Joanne J. Bronson, Nicholas J. Lodge, John E. Macor, James E. Grace, Richard A. Hartz, Vivekananda M. Vrudhula, and Vijay T. Ahuja
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010405 organic chemistry ,Chemistry ,Organic Chemistry ,Clinical Biochemistry ,Crf1 receptor ,Antagonist ,Pharmaceutical Science ,Prodrug ,Pharmacology ,030226 pharmacology & pharmacy ,01 natural sciences ,Biochemistry ,0104 chemical sciences ,Bioavailability ,03 medical and health sciences ,0302 clinical medicine ,Pharmacokinetics ,Drug Discovery ,Aqueous solubility ,Alkoxy group ,Molecular Medicine ,Molecular Biology ,Linker - Abstract
A series of phosphate and ester-based prodrugs of anilinopyrazinone 1 (BMS-665053) containing either a methylene or an (acyloxy)alkoxy linker was prepared and evaluated in rat pharmacokinetic studies with the goal of improving the oral bioavailability of the parent (1). The prodrugs, in general, had improved aqueous solubility and oral bioavailability compared to 1. Prodrug 12, which contains an (acyloxy)alkoxy linker, showed the greatest improvement in the oral bioavailability relative to the parent (1), with a seven-fold increase (from 5% to 36%) in rat pharmacokinetic studies.
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- 2017
13. Triazolopyridine ethers as potent, orally active mGlu2 positive allosteric modulators for treating schizophrenia
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Valerie J. Whiterock, Amy Easton, Regina Miller, Lawrence R. Marcin, Meredith Ferrante, Bradley C. Pearce, John B. Hogan, Joanne J. Bronson, Clotilde Bourin, Mendi A. Higgins, Robert G. Gentles, F. Christopher Zusi, Walter Kostich, John E. Macor, Michael Gulianello, Min Ding, Linda J. Bristow, Adam Hendricson, Kim A. Johnson, Andrew Alt, Yanling Huang, and Matthew A. Seager
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Allosteric modulator ,Chemistry ,Organic Chemistry ,Clinical Biochemistry ,Allosteric regulation ,Pharmaceutical Science ,Plasma protein binding ,Pharmacology ,medicine.disease ,Biochemistry ,In vitro ,030227 psychiatry ,03 medical and health sciences ,0302 clinical medicine ,Oral administration ,Schizophrenia ,Drug Discovery ,Lipophilicity ,medicine ,Molecular Medicine ,Triazolopyridine ,Molecular Biology ,030217 neurology & neurosurgery - Abstract
Triazolopyridine ethers with mGlu2 positive allosteric modulator (PAM) activity are disclosed. The synthesis, in vitro activity, and metabolic stability data for a series of analogs is provided. The effort resulted in the discovery of a potent, selective, and brain penetrant lead molecule BMT-133218 ((+)-7m). After oral administration at 10mg/kg, BMT-133218 demonstrated full reversal of PCP-stimulated locomotor activity and prevented MK-801-induced working memory deficits in separate mouse models. Also, reversal of impairments in executive function were observed in rat set-shifting studies at 3 and 10mg/kg (p.o.). Extensive plasma protein binding as the result of high lipophilicity likely limited activity at lower doses. Optimized triazolopyridine ethers offer utility as mGlu2 PAMs for the treatment of schizophrenia and merit further preclinical investigation.
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- 2017
14. Difluorocyclobutylacetylenes as positive allosteric modulators of mGluR5 with reduced bioactivation potential
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Andrew P. Degnan, Valerie J. Whiterock, Darrell Maxwell, Umesh Hanumegowda, Digavalli V. Sivarao, Anand Balakrishnan, Eric Shields, Joanne J. Bronson, Jeffrey M. Brown, Ryan Westphal, Amy Easton, Arun K. Senapati, Xiaoliang Zhuo, John E. Macor, Kenneth S. Santone, Michael Gulianello, Regina Miller, and Melissa Hill-Drzewi
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0301 basic medicine ,Pyridines ,Receptor, Metabotropic Glutamate 5 ,Clinical Biochemistry ,Allosteric regulation ,Pharmaceutical Science ,Pharmacology ,Biochemistry ,Compound 32 ,Mice ,Structure-Activity Relationship ,03 medical and health sciences ,Allosteric Regulation ,mental disorders ,Drug Discovery ,Animals ,Humans ,Novel object recognition ,Receptor ,Molecular Biology ,Oxazolidinones ,Brain uptake ,Dose-Response Relationship, Drug ,Molecular Structure ,Metabotropic glutamate receptor 5 ,Chemistry ,Organic Chemistry ,Rats ,030104 developmental biology ,nervous system ,Molecular Medicine ,NMDA receptor ,Function (biology) - Abstract
Schizophrenia is a serious illness that affects millions of patients and has been associated with N-methyl-d-aspartate receptor (NMDAR) hypofunction. It has been demonstrated that activation of metabotropic glutamate receptor 5 (mGluR5) enhances NMDA receptor function, suggesting the potential utility of mGluR5 positive allosteric modulators (PAMs) in the treatment of schizophrenia. Herein we describe the optimization of an mGluR5 PAM by replacement of a phenyl with aliphatic heterocycles and carbocycles as a strategy to reduce bioactivation in a biaryl acetylene chemotype. Replacement with a difluorocyclobutane followed by further optimization culminated in the identification of compound 32, a low fold shift PAM with reduced bioactivation potential. Compound 32 demonstrated favorable brain uptake and robust efficacy in mouse novel object recognition (NOR) at low doses.
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- 2016
15. Discovery of Indazoles as Potent, Orally Active Dual Neurokinin 1 Receptor Antagonists and Serotonin Transporter Inhibitors for the Treatment of Depression
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Amy Newton, Joanna Hu, Thorsten Rosner, George O. Tora, Yu-Wen Li, Joseph Raybon, Yi Hsiao, Xiaoping Hou, Joanne J. Bronson, Nicholas J. Lodge, John E. Macor, David A. Conlon, Carl D. Davis, Jung-Hui Sun, Michael K. Wong, Kevin W. Gillman, Sarah J. Taylor, Umesh Hanumegowda, Rudolph G. Krause, Huiping Zhang, Hong Huang, Matthew T. Taber, Andrew P. Degnan, and Rick L. Pieschl
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0301 basic medicine ,Indazoles ,Physiology ,Cognitive Neuroscience ,hERG ,Drug Evaluation, Preclinical ,Administration, Oral ,Pharmacology ,Biochemistry ,Mice ,Structure-Activity Relationship ,03 medical and health sciences ,0302 clinical medicine ,Neurokinin-1 Receptor Antagonists ,Transcriptional Regulator ERG ,In vivo ,Drug Discovery ,Animals ,Humans ,Serotonin Uptake Inhibitors ,Receptor ,Serotonin transporter ,Serotonin Plasma Membrane Transport Proteins ,Depressive Disorder ,Dose-Response Relationship, Drug ,Molecular Structure ,biology ,Drug discovery ,Chemistry ,Cell Biology ,General Medicine ,Receptors, Neurokinin-1 ,Antidepressive Agents ,Rats ,Disease Models, Animal ,030104 developmental biology ,biology.protein ,Gerbillinae ,Reuptake inhibitor ,Selective Serotonin Reuptake Inhibitors ,030217 neurology & neurosurgery - Abstract
Combination studies of neurokinin 1 (NK1) receptor antagonists and serotonin-selective reuptake inhibitors (SSRIs) have shown promise in preclinical models of depression. Such a combination may offer important advantages over the current standard of care. Herein we describe the discovery and optimization of an indazole-based chemotype to provide a series of potent dual NK1 receptor antagonists/serotonin transporter (SERT) inhibitors to overcome issues of ion channel blockade. This effort culminated in the identification of compound 9, an analogue that demonstrated favorable oral bioavailability, excellent brain uptake, and robust in vivo efficacy in a validated depression model. Over the course of this work, a novel heterocycle-directed asymmetric hydrogenation was developed to facilitate installation of the key stereogenic center.
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- 2016
16. Development of 1H-Pyrazolo[3,4-b]pyridines as Metabotropic Glutamate Receptor 5 Positive Allosteric Modulators
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Valerie J. Whiterock, John E. Macor, Joanne J. Bronson, Melissa Hill-Drzewi, Regina Miller, Lizbeth Gallagher, Thaddeus F. Molski, Amy Easton, Xiaoliang Zhuo, Matthew D. Hill, Andrew P. Degnan, Xiaojun Han, Jeffrey M. Brown, Robert L. Bertekap, Haiquan Fang, Michael Gulianello, Michele Matchett, Kenneth S. Santone, and Anand Balakrishnan
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0301 basic medicine ,010405 organic chemistry ,Metabotropic glutamate receptor 5 ,Metabotropic glutamate receptor 4 ,Organic Chemistry ,Allosteric regulation ,Metabotropic glutamate receptor 7 ,Pharmacology ,Biology ,01 natural sciences ,Biochemistry ,0104 chemical sciences ,03 medical and health sciences ,030104 developmental biology ,mental disorders ,Drug Discovery ,NMDA receptor ,Metabotropic glutamate receptor 1 ,Metabotropic glutamate receptor 3 ,Metabotropic glutamate receptor 2 ,Neuroscience - Abstract
The metabotropic glutamate receptor 5 (mGluR5) is an attractive target for the treatment of schizophrenia due to its role in regulating glutamatergic signaling in association with the N-methyl-d-aspartate receptor (NMDAR). We describe the synthesis of 1H-pyrazolo[3,4-b]pyridines and their utility as mGluR5 positive allosteric modulators (PAMs) without inherent agonist activity. A facile and convergent synthetic route provided access to a structurally diverse set of analogues that contain neither the aryl-acetylene-aryl nor aryl-methyleneoxy-aryl elements, the predominant structural motifs described in the literature. Binding studies suggest that members of our new chemotype do not engage the receptor at the MPEP and CPPHA mGluR5 allosteric sites. SAR studies culminated in the first non-MPEP site PAM, 1H-pyrazolo[3,4-b]pyridine 31 (BMT-145027), to improve cognition in a preclinical rodent model of learning and memory.
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- 2016
17. Inhibition of AAK1 Kinase as a Novel Therapeutic Approach to Treat Neuropathic Pain
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James E. Grace, Brian Zambrowicz, Pradeep Vattikundala, Kenneth G. Carson, Jonathan Lippy, Clotilde Bourin, Alan Main, Alan Wilson, Sreenivasulu Naidu, Sandhya Mandlekar, Carolyn Diane Dzierba, Saravanan Elavazhagan, Walter Kostich, Gauri Shankar, Jeffrey M. Brown, Charles M. Conway, Charles F. Albright, Justin Vijay Louis, Yu-Wen Li, Vivek Sharma, Yanling Huang, Laszlo Kiss, Amr Nouraldeen, Susheel J. Nara, Martin A. Lewis, Ryan Westphal, Vinay K. Holenarsipur, Anand Balakrishnan, Amy Easton, Robert Zaczek, Jonathan C. Swaffield, Ted Molski, Rick L. Pieschl, Kevin Baker, Katerina Savelieva, Yingzhi Bi, Kenneth S. Santone, Linda J. Bristow, John E. Macor, Jianlin Feng, Guilan Ye, Joanne J. Bronson, Manish Lal Das, Reeba K. Vikramadithyan, Kevin O’Malley, Jason W. Allen, Brian D. Hamman, Michael Gulianello, Yifeng Lu, Thomas H. Lanthorn, Kimberley A. Lentz, Anoop Kumar, Manoj Dokania, Kumaran Dandapani, and Rex Denton
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0301 basic medicine ,Male ,Nociception ,medicine.drug_class ,Stimulation ,Pharmacology ,Protein Serine-Threonine Kinases ,03 medical and health sciences ,Drug Discovery and Translational Medicine ,Gene Knockout Techniques ,Mice ,0302 clinical medicine ,Opioid receptor ,medicine ,Animals ,Humans ,Receptor ,Protein Kinase Inhibitors ,business.industry ,medicine.disease ,Electrophysiological Phenomena ,Rats ,030104 developmental biology ,Peripheral neuropathy ,HEK293 Cells ,Phenotype ,Opioid ,Spinal Cord ,Neuropathic pain ,Knockout mouse ,Molecular Medicine ,Neuralgia ,business ,030217 neurology & neurosurgery ,medicine.drug - Abstract
To identify novel targets for neuropathic pain, 3097 mouse knockout lines were tested in acute and persistent pain behavior assays. One of the lines from this screen, which contained a null allele of the adapter protein-2 associated kinase 1 (AAK1) gene, had a normal response in acute pain assays (hot plate, phase I formalin), but a markedly reduced response to persistent pain in phase II formalin. AAK1 knockout mice also failed to develop tactile allodynia following the Chung procedure of spinal nerve ligation (SNL). Based on these findings, potent, small-molecule inhibitors of AAK1 were identified. Studies in mice showed that one such inhibitor, LP-935509, caused a reduced pain response in phase II formalin and reversed fully established pain behavior following the SNL procedure. Further studies showed that the inhibitor also reduced evoked pain responses in the rat chronic constriction injury (CCI) model and the rat streptozotocin model of diabetic peripheral neuropathy. Using a nonbrain-penetrant AAK1 inhibitor and local administration of an AAK1 inhibitor, the relevant pool of AAK1 for antineuropathic action was found to be in the spinal cord. Consistent with these results, AAK1 inhibitors dose-dependently reduced the increased spontaneous neural activity in the spinal cord caused by CCI and blocked the development of windup induced by repeated electrical stimulation of the paw. The mechanism of AAK1 antinociception was further investigated with inhibitors of α2 adrenergic and opioid receptors. These studies showed that α2 adrenergic receptor inhibitors, but not opioid receptor inhibitors, not only prevented AAK1 inhibitor antineuropathic action in behavioral assays, but also blocked the AAK1 inhibitor-induced reduction in spinal neural activity in the rat CCI model. Hence, AAK1 inhibitors are a novel therapeutic approach to neuropathic pain with activity in animal models that is mechanistically linked (behaviorally and electrophysiologically) to α2 adrenergic signaling, a pathway known to be antinociceptive in humans.
- Published
- 2016
18. Synthesis and evaluation of carbamate and aryl ether substituted pyrazinones as corticotropin releasing factor-1 (CRF1) receptor antagonists
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Kimberley A. Lentz, Gail K. Mattson, James E. Grace, Nicholas J. Lodge, John E. Macor, Richard A. Hartz, Thaddeus F. Molski, Vijay T. Ahuja, and Joanne J. Bronson
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Carbamate ,Stereochemistry ,Chemistry ,Aryl ,medicine.medical_treatment ,Organic Chemistry ,Clinical Biochemistry ,Pharmaceutical Science ,Ether ,030226 pharmacology & pharmacy ,Biochemistry ,In vitro ,Corticotropin-releasing hormone receptor 1 ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Drug Discovery ,medicine ,Molecular Medicine ,Structure–activity relationship ,Receptor ,Molecular Biology ,IC50 ,030217 neurology & neurosurgery - Abstract
A series of pyrazinone-based compounds incorporating either carbamate or aryl ether groups was synthesized and evaluated as corticotropin-releasing factor-1 (CRF1) receptor antagonists. Structure-activity relationship studies led to the identification of highly potent CRF1 receptor antagonists 14a (IC50=0.74 nM) and 14b (IC50=1.9 nM). The synthesis, structure-activity relationships and in vitro metabolic stability properties of compounds in this series will be described.
- Published
- 2016
19. Biochemical and behavioral effects of PDE10A inhibitors: Relationship to target site occupancy
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Nicholas J. Lodge, John E. Macor, Matthew A. Seager, Samuel Gerritz, Shaun Langdon, Robert Zaczek, Joanne J. Bronson, Alda Fernandes, Karen Heman, James R. Merritt, Yuan Tian, Ryan Westphal, Yang Hong, Annapurna Pendri, Lizbeth Gallagher, Trevor Wojcik, Chongwu Zhang, Yu-Wen Li, and Thaddeus F. Molski
- Subjects
Male ,0301 basic medicine ,Phosphodiesterase Inhibitors ,Striatum ,Pharmacology ,Hippocampal formation ,Medium spiny neuron ,Mice ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,0302 clinical medicine ,Basal ganglia ,Radioligand ,Animals ,Binding site ,Mice, Knockout ,Binding Sites ,Behavior, Animal ,Dose-Response Relationship, Drug ,Phosphoric Diester Hydrolases ,Chemistry ,Brain ,Phosphodiesterase ,Macaca fascicularis ,030104 developmental biology ,PDE10A ,030217 neurology & neurosurgery ,Antipsychotic Agents - Abstract
Phosphodiesterase 10A (PDE10A) inhibitors increase the functionality of striatal medium spiny neurons and produce antipsychotic-like effects in rodents by blocking PDE10A mediated hydrolysis of cAMP and/or cGMP. In the current study, we characterized a radiolabeled PDE10A inhibitor, [(3)H]BMS-843496, and developed an ex vivo PDE10 binding autoradiographic assay to explore the relationship between PDE10 binding site occupancy and the observed biochemical and behavioral effects of PDE10 inhibitors in mice. [(3)H]BMS-843496 is a potent PDE10A inhibitor with a binding affinity (KD) of 0.15 nM and a functional selectivity of >100-fold over other PDE subtypes tested. Specific [(3)H]BMS-843496 binding sites were dominant in the basal ganglia, especially the striatum, with low to moderate binding in the cortical and hippocampal areas, of the mouse and monkey brain. Systemic administration of PDE10 inhibitors produced a dose- and plasma/brain concentration-dependent increase in PDE10A occupancy measured in the striatum. PDE10A occupancy was positively correlated with striatal pCREB expression levels. PDE10A occupancy was also correlated with antipsychotic-like effects measured using the conditioned avoidance response model; a minimum of ∼40% occupancy was typically required to achieve efficacy. In contrast, a clear relationship between PDE10A occupancy and catalepsy scores, a potential extrapyramidal symptom readout in rodent, was not evident.
- Published
- 2016
20. The discovery of VU0652957 (VU2957, Valiglurax): SAR and DMPK challenges en route to an mGlu
- Author
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Joseph D, Panarese, Darren W, Engers, Yong-Jin, Wu, Jason M, Guernon, Aspen, Chun, Alison R, Gregro, Aaron M, Bender, Rory A, Capstick, Joshua M, Wieting, Joanne J, Bronson, John E, Macor, Ryan, Westphal, Matthew, Soars, Julie E, Engers, Andrew S, Felts, Alice L, Rodriguez, Kyle A, Emmitte, Carrie K, Jones, Anna L, Blobaum, P Jeffrey, Conn, Colleen M, Niswender, Corey R, Hopkins, and Craig W, Lindsley
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Structure-Activity Relationship ,Allosteric Regulation ,Dose-Response Relationship, Drug ,Molecular Structure ,Drug Discovery ,Humans ,Isoquinolines ,Receptors, Metabotropic Glutamate ,Heterocyclic Compounds, 2-Ring ,Myotonin-Protein Kinase - Abstract
This letter describes the first account of the chemical optimization (SAR and DMPK profiling) of a new series of mGlu
- Published
- 2018
21. Discovery and characterization of N-(1,3-dialkyl-1H-indazol-6-yl)-1H-pyrazolo[4,3-b]pyridin-3-amine scaffold as mGlu
- Author
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Darren W, Engers, Sean R, Bollinger, Julie L, Engers, Joseph D, Panarese, Megan M, Breiner, Alison, Gregro, Anna L, Blobaum, Joanne J, Bronson, Yong-Jin, Wu, John E, Macor, Alice L, Rodriguez, Rocio, Zamorano, P Jeffrey, Conn, Craig W, Lindsley, Colleen M, Niswender, and Corey R, Hopkins
- Subjects
Antiparkinson Agents ,Structure-Activity Relationship ,Allosteric Regulation ,Cytochrome P-450 CYP1A2 ,Pyridines ,Enzyme Induction ,Cytochrome P-450 CYP1A2 Inducers ,Drug Discovery ,Animals ,Humans ,Pyrazoles ,Receptors, Metabotropic Glutamate ,Rats - Abstract
Previous reports from our laboratory disclosed the structure and activity of a novel 1H-pyrazolo[4,3-b]pyridine-3-amine scaffold (VU8506) which showed excellent potency, selectivity and in vivo efficacy in preclinical rodent models of Parkinson's disease. Unfortunately, this compound suffered from significant CYP1A2 induction as measured through upstream AhR activation (125-fold) and thus was precluded from further advancement in chronic studies. Herein, we report a new scaffold developed recently which was systematically studied in order to mitigate the CYP1A2 liabilities presented in the earlier scaffolds. We have identified a novel structure that maintains the potency and selectivity of other mGlu
- Published
- 2018
22. BMS-986163, a Negative Allosteric Modulator of GluN2B with Potential Utility in Major Depressive Disorder
- Author
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Arvind Mathur, Rajareddy Kallem, Thaddeus F. Molski, Manjunatha Narayana Rao Kamble, Michelle Nophsker, Huiping Zhang, Murali Subramanian, Dalton King, Linda J. Bristow, Lawrence R. Marcin, B.N. Srikumar, Grandhi Venkat Ram Krishna Mohan Gupta, Kumar Kuchibhotla Vijaya, Jayakumar Sankara Warrier, Michael Sinz, Charulatha Sanmathi, G. Nagaraju, Xiaoliang Zhuo, Raju Mannoori, Imadul Islam, Alicia Ng, Pattipati S. Naidu, Eric Shields, Joanne J. Bronson, Narasimharaju Kalidindi, Reeba K. Vikramadithyan, Gopikishan Tonukunuru, Lorin A. Thompson, James Kempson, Srinivasan Thangathirupathy, Jogi Srinivas, Bradley C. Pearce, Jyoti Gulia, Jean Simmermacher, Srinivas Cheruku, Mahesh Paschapur, Jianliang Shi, John E. Macor, Jayant Aher, Manjunath Ramarao, Charlie F. Albright, Richard E. Olson, Rex Denton, Aliphedi B. Reddy, Hyunsoo Park, Karageorge George N, Tanmaya Bastia, and Jianqing Li
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0301 basic medicine ,Allosteric modulator ,Chemistry ,Organic Chemistry ,Allosteric regulation ,Pharmacology ,Prodrug ,medicine.disease ,Biochemistry ,In vitro ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,In vivo ,Drug Discovery ,medicine ,Major depressive disorder ,IC50 ,030217 neurology & neurosurgery ,Ex vivo - Abstract
[Image: see text] There is a significant unmet medical need for more efficacious and rapidly acting antidepressants. Toward this end, negative allosteric modulators of the N-methyl-d-aspartate receptor subtype GluN2B have demonstrated encouraging therapeutic potential. We report herein the discovery and preclinical profile of a water-soluble intravenous prodrug BMS-986163 (6) and its active parent molecule BMS-986169 (5), which demonstrated high binding affinity for the GluN2B allosteric site (K(i) = 4.0 nM) and selective inhibition of GluN2B receptor function (IC(50) = 24 nM) in cells. The conversion of prodrug 6 to parent 5 was rapid in vitro and in vivo across preclinical species. After intravenous administration, compounds 5 and 6 have exhibited robust levels of ex vivo GluN2B target engagement in rodents and antidepressant-like activity in mice. No significant off-target activity was observed for 5, 6, or the major circulating metabolites met-1 and met-2. The prodrug BMS-986163 (6) has demonstrated an acceptable safety and toxicology profile and was selected as a preclinical candidate for further evaluation in major depressive disorder.
- Published
- 2018
23. 2017 Medicinal Chemistry Reviews
- Author
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Joanne J. Bronson
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Engineering ,Traditional medicine ,business.industry ,business - Published
- 2017
24. Biaryls as potent, tunable dual neurokinin 1 receptor antagonists and serotonin transporter inhibitors
- Author
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Kelly Krause, Andrew P. Degnan, George O. Tora, Yu-Wen Li, Daniel G. Morgan, Ramkumar Rajamani, Joanna Hu, Ying Han, Rudolph G. Krause, Joanne J. Bronson, Robert L. Bertekap, Sarah J. Taylor, Kevin W. Gillman, Nicholas J. Lodge, Matthew T. Taber, John E. Macor, Gail K. Mattson, Melissa A. Cunningham, and Carl D. Davis
- Subjects
Serotonin ,medicine.medical_specialty ,Clinical Biochemistry ,Pharmaceutical Science ,Pharmacology ,Gerbil ,Biochemistry ,Neurokinin-1 Receptor Antagonists ,Internal medicine ,Drug Discovery ,Tachykinin receptor 1 ,medicine ,Animals ,Humans ,Receptor ,Molecular Biology ,Serotonin transporter ,Serotonin Plasma Membrane Transport Proteins ,biology ,Depression ,Chemistry ,Biphenyl Compounds ,Organic Chemistry ,Brain ,Antidepressive Agents ,Bioavailability ,Endocrinology ,biology.protein ,Molecular Medicine ,Antidepressant ,Gerbillinae ,Reuptake inhibitor ,Selective Serotonin Reuptake Inhibitors ,Ex vivo - Abstract
Depression is a serious illness that affects millions of patients. Current treatments are associated with a number of undesirable side effects. Neurokinin 1 receptor (NK1R) antagonists have recently been shown to potentiate the antidepressant effects of serotonin-selective reuptake inhibitors (SSRIs) in a number of animal models. Herein we describe the optimization of a biaryl chemotype to provide a series of potent dual NK1R antagonists/serotonin transporter (SERT) inhibitors. Through the choice of appropriate substituents, the SERT/NK1R ratio could be tuned to afford a range of target selectivity profiles. This effort culminated in the identification of an analog that demonstrated oral bioavailability, favorable brain uptake, and efficacy in the gerbil foot tap model. Ex vivo occupancy studies with compound 58 demonstrated the ability to maintain NK1 receptor saturation (>88% occupancy) while titrating the desired level of SERT occupancy (11-84%) via dose selection.
- Published
- 2015
25. Design, synthesis, and evaluation of phenylglycinols and phenyl amines as agonists of GPR88
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Zhi Liang, Alan Wilson, Li Dong, Neil T. Burford, David S. Kimball, Kenneth G. Carson, Yingzhi Bi, Yulian Zhang, Bireshwar Dasgupta, Carolyn Diane Dzierba, Richard A. Hartz, James E. Grace, G. Greg Zipp, Soojin Kwon, Martin A. Lewis, Joanne J. Bronson, Cynthia Anne Fink, Amr Nouraldeen, Saadat Aleem, Giovanni Cianchetta, Jiancheng Wang, Ying Liu, Vijay T. Ahuja, Robert L. Bertekap, Jianxin Han, Michael Alan Green, Angela Cacace, Godwin Kumi, Yudith Garcia, Ying Qiao, Meredith Ferrante, John E. Macor, and Ryan Westphal
- Subjects
Agonist ,Dose-Response Relationship, Drug ,Molecular Structure ,medicine.drug_class ,Chemistry ,Organic Chemistry ,Clinical Biochemistry ,Pharmaceutical Science ,Pharmacology ,Biochemistry ,Small molecule ,Receptors, G-Protein-Coupled ,Structure-Activity Relationship ,HEK293 Cells ,Pharmacokinetics ,Design synthesis ,Ethanolamines ,Drug Design ,Drug Discovery ,medicine ,Humans ,Molecular Medicine ,Amines ,Molecular Biology - Abstract
Small molecule modulators of GPR88 activity (agonists, antagonists, or modulators) are of interest as potential agents for the treatment of a variety of psychiatric disorders including schizophrenia. A series of phenylglycinol and phenylamine analogs have been prepared and evaluated for their GPR88 agonist activity and pharmacokinetic (PK) properties.
- Published
- 2015
26. Preclinical Characterization of (
- Author
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Linda J, Bristow, Jyoti, Gulia, Michael R, Weed, Bettadapura N, Srikumar, Yu-Wen, Li, John D, Graef, Pattipati S, Naidu, Charulatha, Sanmathi, Jayant, Aher, Tanmaya, Bastia, Mahesh, Paschapur, Narasimharaju, Kalidindi, Kuchibhotla Vijaya, Kumar, Thaddeus, Molski, Rick, Pieschl, Alda, Fernandes, Jeffrey M, Brown, Digavalli V, Sivarao, Kimberly, Newberry, Mark, Bookbinder, Joseph, Polino, Deborah, Keavy, Amy, Newton, Eric, Shields, Jean, Simmermacher, James, Kempson, Jianqing, Li, Huiping, Zhang, Arvind, Mathur, Raja Reddy, Kallem, Meenakshee, Sinha, Manjunath, Ramarao, Reeba K, Vikramadithyan, Srinivasan, Thangathirupathy, Jayakumar, Warrier, Imadul, Islam, Joanne J, Bronson, Richard E, Olson, John E, Macor, Charlie F, Albright, Dalton, King, Lorin A, Thompson, Lawrence R, Marcin, and Michael, Sinz
- Subjects
Male ,Depressive Disorder, Major ,Xenopus ,Brain ,Dissociative Disorders ,Motor Activity ,Brain Waves ,Receptors, N-Methyl-D-Aspartate ,Antidepressive Agents ,Organophosphates ,Pyrrolidinones ,Rats, Sprague-Dawley ,Macaca fascicularis ,Mice ,Radioligand Assay ,Memory, Short-Term ,Allosteric Regulation ,Piperidines ,Animals ,Administration, Intravenous ,Prodrugs - Abstract
(
- Published
- 2017
27. Synthesis and evaluation of prodrugs of corticotropin-releasing factor-1 (CRF
- Author
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Richard A, Hartz, Vivekananda M, Vrudhula, Vijay T, Ahuja, James E, Grace, Nicholas J, Lodge, Joanne J, Bronson, and John E, Macor
- Subjects
Pyrazines ,Animals ,Biological Availability ,Prodrugs ,Receptors, Corticotropin-Releasing Hormone ,Rats - Abstract
A series of phosphate and ester-based prodrugs of anilinopyrazinone 1 (BMS-665053) containing either a methylene or an (acyloxy)alkoxy linker was prepared and evaluated in rat pharmacokinetic studies with the goal of improving the oral bioavailability of the parent (1). The prodrugs, in general, had improved aqueous solubility and oral bioavailability compared to 1. Prodrug 12, which contains an (acyloxy)alkoxy linker, showed the greatest improvement in the oral bioavailability relative to the parent (1), with a seven-fold increase (from 5% to 36%) in rat pharmacokinetic studies.
- Published
- 2017
28. Synthesis and evaluation of candidate PET radioligands for corticotropin-releasing factor type-1 receptors
- Author
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Masahiro Fujita, Yu Wen Li, Joanne J. Bronson, Heidi Dulac, Robert Zaczek, Jeffrey A. Deskus, Robert B. Innis, Masao Imaizumi, Victor W. Pike, Rick L. Pieschl, Frederick T. Chin, Nicholas J. Lodge, John E. Macor, Sami S. Zoghbi, Thaddeus F. Molski, Douglas D. Dischino, and Ronald J. Mattson
- Subjects
Male ,Cancer Research ,Cerebellum ,medicine.medical_specialty ,Biodistribution ,Chemistry Techniques, Synthetic ,Ligands ,Receptors, Corticotropin-Releasing Hormone ,Article ,Internal medicine ,medicine ,Radioligand ,Animals ,Tissue Distribution ,Radiology, Nuclear Medicine and imaging ,Receptor ,Radiochemistry ,Chemistry ,Brain ,Human brain ,Ligand (biochemistry) ,Macaca mulatta ,In vitro ,Rats ,medicine.anatomical_structure ,Endocrinology ,Positron-Emission Tomography ,Pyrazines ,Molecular Medicine ,Brainstem - Abstract
Introduction A radioligand for measuring the density of corticotropin-releasing factor subtype-1 receptors (CRF 1 receptors) in living animal and human brain with positron emission tomography (PET) would be a useful tool for neuropsychiatric investigations and the development of drugs intended to interact with this target. This study was aimed at discovery of such a radioligand from a group of CRF 1 receptor ligands based on a core 3-(phenylamino)‐pyrazin-2(1 H )-one scaffold. Methods CRF 1 receptor ligands were selected for development as possible PET radioligands based on their binding potency at CRF 1 receptors (displacement of [ 125 I]CRF from rat cortical membranes), measured lipophilicity, autoradiographic binding profile in rat and rhesus monkey brain sections, rat biodistribution, and suitability for radiolabeling with carbon-11 or fluorine-18. Two identified candidates (BMS-721313 and BMS-732098) were labeled with fluorine-18. A third candidate (BMS-709460) was labeled with carbon-11 and all three radioligands were evaluated in PET experiments in rhesus monkey. CRF 1 receptor density ( B max ) was assessed in rhesus brain cortical and cerebellum membranes with the CRF 1 receptor ligand, [ 3 H]BMS-728300. Results The three ligands selected for development showed high binding affinity ( IC 50 values, 0.3–8 nM) at CRF 1 receptors and moderate lipophilicity ( LogD , 2.8–4.4). [ 3 H]BMS-728300 and the two 18 F-labeled ligands showed region-specific binding in rat and rhesus monkey brain autoradiography, namely higher binding density in the frontal and limbic cortex, and cerebellum than in thalamus and brainstem. CRF 1 receptor B max in rhesus brain was found to be 50–120 fmol/mg protein across cortical regions and cerebellum. PET experiments in rhesus monkey showed that the radioligands [ 18 F]BMS-721313, [ 18 F]BMS-732098 and [ 11 C]BMS-709460 gave acceptably high brain radioactivity uptake but no indication of the specific binding as seen in vitro . Conclusions Candidate CRF 1 receptor PET radioligands were identified but none proved to be effective for imaging monkey brain CRF 1 receptors. Higher affinity radioligands are likely required for successful PET imaging of CRF 1 receptors.
- Published
- 2014
29. To Market, To Market--2015
- Author
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Kevin Peese, Ricardo Garcia, Joanne J. Bronson, Bruce A. Ellsworth, Achal Pashine, J. Robert Merritt, Dhar T G Murali, and Franck J. Duclos
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Biology - Published
- 2016
30. NK1 receptor antagonism lowers occupancy requirement for antidepressant-like effects of SSRIs in the Gerbil forced swim test
- Author
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Kimberly Newberry, Kevin W. Gillman, Matthew T. Taber, Snjezana Lelas, Tanya L. Wallace-Boone, Yu-Wen Li, Carl D. Davis, Rick L. Pieschl, Nicholas J. Lodge, John E. Macor, Thaddeus F. Molski, Michael F. Parker, Joanne J. Bronson, and Amy Newton
- Subjects
Male ,Serotonin ,medicine.medical_specialty ,Morpholines ,Serotonin reuptake inhibitor ,Prefrontal Cortex ,Citalopram ,Pharmacology ,Gerbil ,Radioligand Assay ,Cellular and Molecular Neuroscience ,Neurokinin-1 Receptor Antagonists ,Piperidines ,Fluoxetine ,Internal medicine ,medicine ,Animals ,Humans ,Aprepitant ,Serotonin transporter ,Serotonin Plasma Membrane Transport Proteins ,Dose-Response Relationship, Drug ,biology ,Chemistry ,Antagonist ,Drug Synergism ,Immobility Response, Tonic ,Receptors, Neurokinin-1 ,Antidepressive Agents ,HEK293 Cells ,Endocrinology ,biology.protein ,Gerbillinae ,Selective Serotonin Reuptake Inhibitors ,medicine.drug - Abstract
The known interactions between the serotonergic and neurokinin systems suggest that serotonin reuptake inhibitor (SSRIs) efficacy may be improved by neurokinin-1 receptor (NK1R) antagonism. In the current studies combination of a subeffective dose of an SSRI (0.3 mg/kg fluoxetine or 0.03 mg/kg citalopram) with a subeffective dose of an NK1R antagonist (0.3 mg/kg aprepitant or 1 mg/kg CP-122,721) produced efficacy in the gerbil forced swim test (FST). Serotonin transporter (SERT) occupancy produced by 1 mg/kg fluoxetine (lowest efficacious dose) was 52 ± 5% and was reduced to 29 ± 4% at 0.3 mg/kg, a dose that was efficacious in combination with 0.3 mg/kg aprepitant or 1 mg/kg CP-122,721; the corresponding NK1R occupancies were 79 ± 4% and 61 ± 4% for aprepitant and CP-122,721, respectively. For citalopram, SERT occupancy at the lowest efficacious dose (0.1 mg/kg) was 50 ± 4% and was reduced to 20 ± 5% at 0.03 mg/kg, a dose that was efficacious when combined with aprepitant (0.3 mg/kg). Aprepitant (10 mg/kg) augmented the serotonin elevation produced by fluoxetine (1 or 10 mg/kg) in the gerbil prefrontal cortex; i.e. NK1R antagonism can modulate serotonin responses. A novel orally-available dual-acting NK1R antagonist/SERT inhibitor BMS-795176 is described; gerbil Ki = 1.4 and 1 nM at NK1R and SERT, respectively. BMS-795176 was efficacious in the gerbil FST; efficacy was observed with 35 ± 3% SERT occupancy and 73 ± 3% NK1R occupancy. The interaction between NK1R antagonism and SERT inhibition to lower the SERT occupancy required for antidepressant-like efficacy suggests that BMS-795176 has the potential to improve efficacy with a reduction in SSRI-associated side effects.
- Published
- 2013
31. Design, optimization, and in vivo evaluation of a series of pyridine derivatives with dual NK1 antagonism and SERT inhibition for the treatment of depression
- Author
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Yu-Wen Li, George O. Tora, Snjezana Lelas, Kim A. Johnson, Matthew T. Taber, Joanne J. Bronson, Michael F. Parker, Rudolf G. Krause, Amy Newton, Robert L. Bertekap, Kelly D. Lengyel, Kevin W. Gillman, Nicholas J. Lodge, Rick L. Pieschl, John E. Macor, Andrew P. Degnan, Silva Mark, and Sarah J. Taylor
- Subjects
Phenylpiperidine ,Pyridines ,Stereochemistry ,Clinical Biochemistry ,Pharmaceutical Science ,Ether ,Pharmacology ,Gerbil ,Biochemistry ,Inhibitory Concentration 50 ,chemistry.chemical_compound ,Neurokinin-1 Receptor Antagonists ,In vivo ,Drug Discovery ,Pyridine ,Animals ,Receptor ,Molecular Biology ,Molecular Structure ,Depression ,Chemistry ,Organic Chemistry ,Disease Models, Animal ,Drug Design ,Molecular Medicine ,Serotonin Antagonists ,Gerbillinae ,Antagonism ,Behavioural despair test - Abstract
A series of substituted pyridines, ether linked to a phenylpiperidine core were optimized for dual NK(1)/SERT affinity. Optimization based on NK(1)/SERT binding affinities, and minimization of off-target ion channel activity lead to the discovery of compound 44. In vivo evaluation of 44 in the gerbil forced swim test (a depression model), and ex-vivo NK(1)/SERT receptor occupancy data support the potential of a dual acting compound for the treatment of depression.
- Published
- 2013
32. [18F](R)-5-chloro-1-(1-cyclopropyl-2-methoxyethyl)-3-(4-(2-fluoroethoxy)-2,5-dimethyl phenylamino)pyrazin-2(1H)-one: Introduction of N3-phenylpyrazinones as potential CRF-R1 PET imaging agents
- Author
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Julia M. Nielsen, Jennifer McDonald, Dmitry Zuev, Megan Hayes, Eric Wexler, Joanne J. Bronson, Henry Wong, Yu-Wen Li, Nicholas J. Lodge, John E. Macor, Jeffrey A. Deskus, James E. Grace, Hong Huang, Gail K. Mattson, Mary Guaraldi, Derek J. Denhart, David C. Onthank, Vijay T. Ahuja, Heidi Dulac, Michael F. Parker, Larisa Zueva, Douglas D. Dischino, Ronald J. Mattson, Thaddeus F. Molski, Michael Azure, Jonathan L. Ditta, and Richard A. Hartz
- Subjects
Fluorine Radioisotopes ,Clinical Biochemistry ,Pharmaceutical Science ,Pharmacology ,Biochemistry ,Medicinal chemistry ,Imaging, Three-Dimensional ,Drug Discovery ,Radioligand ,Animals ,Tissue Distribution ,Molecular Biology ,Aniline Compounds ,Molecular Structure ,Chemistry ,Organic Chemistry ,Binding properties ,Brain ,Pet imaging ,Metabolic stability ,Rat brain ,Rats ,Positron-Emission Tomography ,Pyrazines ,Lipophilicity ,Pyrazoles ,Molecular Medicine - Abstract
Based on a favorable balance between CRF-R1 affinity, lipophilicity and metabolic stability, compound 10 was evaluated for potential development as PET radioligand. Compound [18F]10 was prepared with high radiochemical purity and showed promising binding properties in rat brain imaging experiments.
- Published
- 2012
33. Triazolopyridine ethers as potent, orally active mGlu
- Author
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Mendi A, Higgins, Lawrence R, Marcin, F, Christopher Zusi, Robert, Gentles, Min, Ding, Bradley C, Pearce, Amy, Easton, Walter A, Kostich, Matthew A, Seager, Clotilde, Bourin, Linda J, Bristow, Kim A, Johnson, Regina, Miller, John, Hogan, Valerie, Whiterock, Michael, Gulianello, Meredith, Ferrante, Yanling, Huang, Adam, Hendricson, Andrew, Alt, John E, Macor, and Joanne J, Bronson
- Subjects
Male ,Models, Molecular ,Dose-Response Relationship, Drug ,Molecular Structure ,Pyridines ,Administration, Oral ,Haplorhini ,Triazoles ,Receptors, Metabotropic Glutamate ,Rats ,Mice, Inbred C57BL ,Rats, Sprague-Dawley ,Disease Models, Animal ,Mice ,Structure-Activity Relationship ,Allosteric Regulation ,Schizophrenia ,Animals ,Ethers - Abstract
Triazolopyridine ethers with mGlu
- Published
- 2016
34. Oxazolidinone-based allosteric modulators of mGluR5: Defining molecular switches to create a pharmacological tool box
- Author
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Arun K. Senapati, Valerie J. Whiterock, Fukang Yang, Lawrence B. Snyder, Andrew P. Degnan, Ryan Westphal, Hong Huang, Gail K. Mattson, Digavalli V. Sivarao, Anand Balakrishnan, Michael Gulianello, Michele Matchett, Eric Shields, Kenneth S. Santone, Joanne J. Bronson, John E. Macor, Amy Easton, Yanling Huang, and Regina Miller
- Subjects
0301 basic medicine ,Agonist ,Allosteric modulator ,Stereochemistry ,medicine.drug_class ,Receptor, Metabotropic Glutamate 5 ,Clinical Biochemistry ,Allosteric regulation ,Pharmaceutical Science ,Convulsants ,Computational biology ,Biochemistry ,03 medical and health sciences ,Mice ,Structure-Activity Relationship ,0302 clinical medicine ,Allosteric Regulation ,Drug Discovery ,medicine ,Structure–activity relationship ,Animals ,Humans ,Molecular Biology ,Oxazolidinones ,Molecular switch ,Metabotropic glutamate receptor 5 ,Chemistry ,Organic Chemistry ,Recognition, Psychology ,Rats ,Mice, Inbred C57BL ,030104 developmental biology ,Molecular Medicine ,Functional activity ,030217 neurology & neurosurgery - Abstract
Herein we describe the structure activity relationships uncovered in the pursuit of an mGluR5 positive allosteric modulator (PAM) for the treatment of schizophrenia. It was discovered that certain modifications of an oxazolidinone-based chemotype afforded predictable changes in the pharmacological profile to give analogs with a wide range of functional activities. The discovery of potent silent allosteric modulators (SAMs) allowed interrogation of the mechanism-based liabilities associated with mGluR5 activation and drove our medicinal chemistry effort toward the discovery of low efficacy (fold shift) PAMs devoid of agonist activity. This work resulted in the identification of dipyridyl 22 (BMS-952048), a compound with a favorable free fraction, efficacy in a rodent-based cognition model, and low potential for convulsions in mouse.
- Published
- 2016
35. Discovery, Synthesis, and Preclinical Characterization of N-(3-Chloro-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridin-3-amine (VU0418506), a Novel Positive Allosteric Modulator of the Metabotropic Glutamate Receptor 4 (mGlu4)
- Author
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Anna L. Blobaum, Yiu Yin Cheung, Jeremy Hurley, Carrie K. Jones, James M. Salovich, Colleen M. Niswender, John E. Macor, Ryan D. Morrison, Pedro M. Garcia-Barrantes, P. Jeffrey Conn, Joanne J. Bronson, Corey R. Hopkins, J. Scott Daniels, Rocco D. Gogliotti, Matthew G. Soars, Craig W. Lindsley, Darren W. Engers, and Xiaoliang Zhuo
- Subjects
0301 basic medicine ,Allosteric modulator ,Physiology ,Stereochemistry ,Pyridines ,Cognitive Neuroscience ,Allosteric regulation ,Receptors, Metabotropic Glutamate ,Biochemistry ,Article ,03 medical and health sciences ,Structure-Activity Relationship ,0302 clinical medicine ,Allosteric Regulation ,In vivo ,Structure–activity relationship ,Animals ,Humans ,Excitatory Amino Acid Agents ,Picolinic Acids ,Chromatography, High Pressure Liquid ,Metabotropic glutamate receptor 5 ,Chemistry ,Metabotropic glutamate receptor 4 ,Cell Biology ,General Medicine ,Amides ,030104 developmental biology ,Metabotropic glutamate receptor 1 ,Pyrazoles ,Metabotropic glutamate receptor 2 ,030217 neurology & neurosurgery - Abstract
The efficacy of positive allosteric modulators (PAMs) of the metabotropic glutamate receptor 4 (mGlu4) in preclinical rodent models of Parkinson’s disease has been established by a number of groups. Here, we report an advanced preclinically characterized mGlu4 PAM, N-(3-chloro-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridin-3-amine (VU0418506). We detail the discovery of VU0418506 starting from a common picolinamide core scaffold and evaluation of a number of amide bioisosteres leading to the novel pyrazolo[4,3-b]pyridine head group. VU0418506 has been characterized as a potent and selective mGlu4 PAM with suitable in vivo pharmacokinetic properties in three preclinical safety species.
- Published
- 2016
36. Synthesis and evaluation of carbamate and aryl ether substituted pyrazinones as corticotropin releasing factor-1 (CRF₁) receptor antagonists
- Author
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Vijay T, Ahuja, Richard A, Hartz, Thaddeus F, Molski, Gail K, Mattson, Kimberley A, Lentz, James E, Grace, Nicholas J, Lodge, Joanne J, Bronson, and John E, Macor
- Subjects
Structure-Activity Relationship ,Cell Line, Tumor ,Pyrazines ,Microsomes, Liver ,Animals ,Humans ,Carbamates ,Receptors, Corticotropin-Releasing Hormone ,Rats - Abstract
A series of pyrazinone-based compounds incorporating either carbamate or aryl ether groups was synthesized and evaluated as corticotropin-releasing factor-1 (CRF1) receptor antagonists. Structure-activity relationship studies led to the identification of highly potent CRF1 receptor antagonists 14a (IC50=0.74 nM) and 14b (IC50=1.9 nM). The synthesis, structure-activity relationships and in vitro metabolic stability properties of compounds in this series will be described.
- Published
- 2016
37. Discovery and Preclinical Evaluation of BMS-955829, a Potent Positive Allosteric Modulator of mGluR5
- Author
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Amy Easton, Jeffrey M. Brown, Valerie J. Whiterock, Yanling Huang, Gail K. Mattson, Kelli M. Jones, Michele Matchett, Arun K. Senapati, Andrew P. Degnan, Frank J. Simutis, Yu-Wen Li, Lawrence B. Snyder, Alda Fernandes, Digavalli V. Sivarao, Anand Balakrishnan, Umesh Hanumegowda, Kenneth S. Santone, Eric Shields, Regina Miller, Joanne J. Bronson, Ryan Westphal, Michael Gulianello, John E. Macor, Hong Huang, and Fukang Yang
- Subjects
0301 basic medicine ,Agonist ,Allosteric modulator ,medicine.drug_class ,Metabotropic glutamate receptor 5 ,Organic Chemistry ,Allosteric regulation ,Neurotoxicity ,Glutamate receptor ,Biology ,Pharmacology ,medicine.disease ,Biochemistry ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Metabotropic glutamate receptor ,mental disorders ,Drug Discovery ,medicine ,Potency ,030217 neurology & neurosurgery - Abstract
Positive allosteric modulators (PAMs) of the metabotropic glutamate receptor subtype 5 (mGluR5) are of interest due to their potential therapeutic utility in schizophrenia and other cognitive disorders. Herein we describe the discovery and optimization of a novel oxazolidinone-based chemotype to identify BMS-955829 (4), a compound with high functional PAM potency, excellent mGluR5 binding affinity, low glutamate fold shift, and high selectivity for the mGluR5 subtype. The low fold shift and absence of agonist activity proved critical in the identification of a molecule with an acceptable preclinical safety profile. Despite its low fold shift, 4 retained efficacy in set shifting and novel object recognition models in rodents.
- Published
- 2016
38. An Efficient, Direct Bis-ortho-chlorination of 4-(Difluoromethoxy)aniline and Its Application to the Synthesis of BMS-665053, a Potent and Selective Pyrazinone-Containing Corticotropin-Releasing Factor-1 Receptor Antagonist
- Author
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Bang-Chi Chen, Vijay T. Ahuja, Daniel Smith, Subramaniam Krishnananthan, Joanne J. Bronson, Bireshwar Dasgupta, Jianqing Li, Richard A. Hartz, William D. Schmitz, Joel C. Barrish, and Arvind Mathur
- Subjects
chemistry.chemical_compound ,Aniline ,chemistry ,medicine.drug_class ,Stereochemistry ,Organic Chemistry ,medicine ,Physical and Theoretical Chemistry ,Receptor antagonist ,Preclinical toxicology ,Medicinal chemistry - Abstract
An efficient scale-up synthesis of (S)-5-chloro-1-(1-cyclopropylethyl)-3-(2,6-dichloro-4-(difluoromethoxy)phenylamino)-pyrazin-2(1H)-one, 1 (BMS-665053), is described. This new process features a one-step direct bis-ortho-chlorination of 4-(difluoromethoxy)aniline with HCl and H2O2, and a palladium-catalyzed coupling of 2,6-dichloro-4-(difluoromethoxy)aniline 2 and (S)-3,5-dichloro-1-(1-cyclopropylethyl)pyrazin-2(1H)-one 3. The process was applied to the preparation of batches of 1 for preclinical toxicology studies.
- Published
- 2012
39. To Market, To Market--2014
- Author
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Bruce A. Ellsworth, Joanne J. Bronson, Amelia Black, J. Robert Merritt, Dhar T G Murali, Kevin Peese, and Achal Pashine
- Subjects
Business - Published
- 2015
40. Potential CRF1R PET imaging agents: N-Fluoroalkyl-8-(6-methoxy-2-methylpyridin-3-yl)-2,7-dimethyl-N-alkylpyrazolo[1,5-a][1,3,5]triazin-4-amines
- Author
-
Hong Huang, Nicholas J. Lodge, John E. Macor, Ronald J. Mattson, Edward S. Kozlowski, Gail K. Mattson, Xiaohua Stella Huang, Julia M. Nielsen, Qi Gao, Joanne J. Bronson, Dedong Wu, Dmitry Zuev, and Larisa Zueva
- Subjects
Nitrile ,Bicyclic molecule ,Triazines ,Stereochemistry ,Organic Chemistry ,Clinical Biochemistry ,Crf1 receptor ,Molecular Conformation ,Pharmaceutical Science ,Pet imaging ,Crystallography, X-Ray ,Ligand (biochemistry) ,Receptors, Corticotropin-Releasing Hormone ,Biochemistry ,Chemical synthesis ,Molecular conformation ,chemistry.chemical_compound ,chemistry ,Positron-Emission Tomography ,Drug Discovery ,Pyrazoles ,Molecular Medicine ,Amines ,Molecular Biology - Abstract
A series of N-fluoroalkyl-8-(6-methoxy-2-methylpyridin-3-yl)-2,7-dimethyl-N-alkylpyrazolo[1,5-a][1,3,5]triazin-4-amines were prepared and evaluated as potential CRF(1)R PET imaging agents. Optimization of their CRF(1)R binding potencies and octanol-phosphate buffer phase distribution coefficients resulted in discovery of analog 7e (IC(50)=6.5 nM, logD=3.5).
- Published
- 2011
41. Chiral separation of potent corticotropin-releasing factor-1 receptor antagonists by supercritical fluid chromatography
- Author
-
Richard A. Hartz, Vivekananda M. Vrudhula, Richard A. Dalterio, David B. Wang-Iverson, Jingfang Qian-Cutrone, Joanne J. Bronson, Vijay T. Ahuja, and Dauh-Rurng Wu
- Subjects
animal structures ,Resolution (mass spectrometry) ,Corticotropin-Releasing Hormone ,Clinical Biochemistry ,Phenylcarbamates ,Substituent ,Pharmaceutical Science ,Receptors, Corticotropin-Releasing Hormone ,Analytical Chemistry ,chemistry.chemical_compound ,Drug Discovery ,Humans ,Organic chemistry ,Receptor ,Spectroscopy ,Alkyl ,chemistry.chemical_classification ,Ethanol ,Chromatography, Supercritical Fluid ,Stereoisomerism ,Chiral resolution ,chemistry ,Pyrazines ,Supercritical fluid chromatography ,Amylose ,Enantiomer - Abstract
Pyrazinones bearing an N-1-alkyl chain with a chiral center have been reported as potent antagonists of the corticotropin-releasing factor-1 receptor (CRF1R). Separation of individual enantiomers for preclinical testing was an important aspect of lead optimization. To evaluate the applicability and efficiency of supercritical fluid chromatography (SFC) for enantiomeric resolution of this class of compounds, enantiomeric pairs of eight pyrazinones with different structural characteristics were tested under an array of SFC conditions. The results showed that pyrazinones with a 1-cyclopropyl-2-methoxyethyl substituent were readily separated with a Chiralpak AD-H or Chiralcel OD-H column with ethanol as the modifier. On the other hand, analogs with a less polar alkyl substituent were not amenable to the general method and required further optimization of the chromatographic conditions. In addition, structural variations on the pyrazinone core and aromatic moiety had an impact on the chiral resolution of this class of compounds. This investigation led to the development of efficient chiral SFC methods for separating all eight pyrazinone enantiomeric pairs encompassing an array of structural variations.
- Published
- 2011
42. 5-Arylamino-1,2,4-triazin-6(1H)-one CRF1 receptor antagonists
- Author
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Xiaoliang Zhuo, Joanne J. Bronson, Thaddeus F. Molski, Corrine R. Griffin, William D. Schmitz, Yu-Wen Li, Richard E. Olson, Allison B. Brenner, Jonathan L. Ditta, Nicholas J. Lodge, and John E. Macor
- Subjects
Triazines ,Chemistry ,Stereochemistry ,Organic Chemistry ,Clinical Biochemistry ,Crf1 receptor ,Pharmaceutical Science ,Oxidative phosphorylation ,Ring (chemistry) ,Receptors, Corticotropin-Releasing Hormone ,Biochemistry ,Rats ,Inhibitory Concentration 50 ,Structure-Activity Relationship ,Pyrazines ,Drug Discovery ,Animals ,Humans ,Molecular Medicine ,Receptor ,Oxidation-Reduction ,Molecular Biology - Abstract
A series of 5-arylamino-1,2,4-triazin-6(1H)-ones was synthesized and evaluated as antagonists at the corticotropin releasing factor receptor. Formation of CYP-mediated oxidative reactive metabolites previously observed in a related N3-phenylpyrazinone structure was minimized by incorporation of the additional ring nitrogen found in the triazinones.
- Published
- 2010
43. Synthesis and structure–activity relationships of N3-pyridylpyrazinones as corticotropin-releasing factor-1 (CRF1) receptor antagonists
- Author
-
Joanne J. Bronson, Gail K. Mattson, William D. Schmitz, Richard A. Hartz, Vijay T. Ahuja, Nicholas J. Lodge, John E. Macor, and Thaddeus F. Molski
- Subjects
Stereochemistry ,Chemistry ,organic chemicals ,Organic Chemistry ,Clinical Biochemistry ,Crf1 receptor ,Pharmaceutical Science ,Receptors, Corticotropin-Releasing Hormone ,Biochemistry ,Structure-Activity Relationship ,Pyrazines ,parasitic diseases ,Drug Discovery ,Molecular Medicine ,heterocyclic compounds ,Receptor ,Molecular Biology ,G protein-coupled receptor - Abstract
A series of N3-pyridylpyrazinones was investigated as corticotropin-releasing factor-1 receptor antagonists. It was observed that the binding affinity of analogues containing a pyridyl group was influenced not only by the substitution pattern on the pyridyl group, but also by the pKa of the pyridyl nitrogen. Analogues containing a novel 6-(difluoromethoxy)-2,5-dimethylpyridin-3-amine group were among the most potent N3-pyridylpyrazinones synthesized. The synthesis and SAR of N3-pyridylpyrazinones is described herein.
- Published
- 2010
44. In Vitro Intrinsic Clearance-Based Optimization of N3-Phenylpyrazinones as Corticotropin-Releasing Factor-1 (CRF1) Receptor Antagonists
- Author
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Yu-Wen Li, Harvey Wong, Allison B. Brenner, James E. Grace, Jianqing Li, Maria Rafalski, Nicholas J. Lodge, Macor John E, Ronald J. Mattson, Jonathan L. Ditta, Thaddeus F. Molski, Joanne J. Bronson, Vijay T. Ahuja, Robert Zaczek, Richard A. Hartz, Snjezana Lelas, Argyrios G. Arvanitis, Jeffrey A. Deskus, Kimberley A. Lentz, Richard E. Olson, Andrew P. Combs, William D. Schmitz, Eddy W. Yue, and Derek J. Denhart
- Subjects
Male ,Metabolic Clearance Rate ,Chemistry ,Antagonist ,Pharmacology ,Receptors, Corticotropin-Releasing Hormone ,Rats ,Corticotropin-releasing hormone receptor 1 ,Bioavailability ,Inhibitory Concentration 50 ,Biochemistry ,Pharmacokinetics ,In vivo ,Oral administration ,Pyrazines ,Drug Discovery ,Animals ,Humans ,Molecular Medicine ,Receptor ,IC50 - Abstract
A series of pyrazinone-based heterocycles was identified as potent and orally active corticotropin-releasing factor-1 (CRF(1)) receptor antagonists. Selected compounds proved efficacious in an anxiety model in rats; however, pharmacokinetic properties were not optimal. In this article, we describe an in vitro intrinsic clearance-based approach to the optimization of pyrazinone-based CRF(1) receptor antagonists wherein sites of metabolism were identified by incubation with human liver microsomes. It was found that the rate of metabolism could be decreased by incorporation of appropriate substituents at the primary sites of metabolism. This led to the discovery of compound 12x, a highly potent (IC(50) = 1.0 nM) and selective CRF(1) receptor antagonist with good oral bioavailability (F = 52%) in rats and efficacy in the defensive withdrawal anxiety test in rats.
- Published
- 2009
45. The Amyloid-β Rise and γ-Secretase Inhibitor Potency Depend on the Level of Substrate Expression
- Author
-
Bergstrom Carl P, Jeremy H. Toyn, Robert H. Grafstrom, Yang Michael G, Mcelhone Katharine E, Michael J. Ford, Cathy J. Kieras, Yang Cao, Dietmar A. Seiffert, Richard E. Olson, Lawrence G. Iben, Charles F. Albright, Joseph L. Cantone, Craig Polson, Maria Pierdomenico, Jason A. Corsa, Dieter M. Drexler, John E. Macor, Jere E. Meredith, Margi E. Goldstein, Lisa M. Sisk, Mark W. Thompson, Joanne J. Bronson, Arthur H. Roach, Catherine R. Burton, Tracey Fiedler, Carol M. Krause, Robert Zaczek, Yuval Blat, Donna M. Barten, Andrew M. Stern, and Xu-Alan Lin
- Subjects
Endocytic cycle ,Peptide ,Cleavage (embryo) ,Biochemistry ,Gene Expression Regulation, Enzymologic ,Cell Line ,Substrate Specificity ,Mice ,medicine ,Animals ,Humans ,Potency ,Secretion ,Enzyme Inhibitors ,Molecular Biology ,chemistry.chemical_classification ,Amyloid beta-Peptides ,Hydrocarbons, Halogenated ,Brain ,Cell Biology ,medicine.disease ,Protein Structure, Tertiary ,Rats ,Butyrates ,Enzyme ,chemistry ,Cell culture ,Biophysics ,Female ,Amyloid Precursor Protein Secretases ,Alzheimer's disease ,Protein Binding - Abstract
The amyloid-beta (Abeta) peptide, which likely plays a key role in Alzheimer disease, is derived from the amyloid-beta precursor protein (APP) through consecutive proteolytic cleavages by beta-site APP-cleaving enzyme and gamma-secretase. Unexpectedly gamma-secretase inhibitors can increase the secretion of Abeta peptides under some circumstances. This "Abeta rise" phenomenon, the same inhibitor causing an increase in Abeta at low concentrations but inhibition at higher concentrations, has been widely observed. Here we show that the Abeta rise depends on the beta-secretase-derived C-terminal fragment of APP (betaCTF) or C99 levels with low levels causing rises. In contrast, the N-terminally truncated form of Abeta, known as "p3," formed by alpha-secretase cleavage, did not exhibit a rise. In addition to the Abeta rise, low betaCTF or C99 expression decreased gamma-secretase inhibitor potency. This "potency shift" may be explained by the relatively high enzyme to substrate ratio under conditions of low substrate because increased concentrations of inhibitor would be necessary to affect substrate turnover. Consistent with this hypothesis, gamma-secretase inhibitor radioligand occupancy studies showed that a high level of occupancy was correlated with inhibition of Abeta under conditions of low substrate expression. The Abeta rise was also observed in rat brain after dosing with the gamma-secretase inhibitor BMS-299897. The Abeta rise and potency shift are therefore relevant factors in the development of gamma-secretase inhibitors and can be evaluated using appropriate choices of animal and cell culture models. Hypothetical mechanisms for the Abeta rise, including the "incomplete processing" and endocytic models, are discussed.
- Published
- 2008
46. Antibacterial Pleuromutilin Derivatives based on Alternate Core Structures:Arigoni and Birch Chemistry Revisited
- Author
-
Joanne J. Bronson, Stella Huang, Dane M. Springer, Qi Gao, Goodrich Jason, Kenneth DenBleyker, Thomas J. Dougherty, Bing-Yu Luh, and Joan Fung-Tomc
- Subjects
chemistry.chemical_compound ,Chemistry ,Drug Discovery ,Core (graph theory) ,Pharmaceutical Science ,Molecular Medicine ,Combinatorial chemistry ,Pleuromutilin - Published
- 2008
47. N-(5-Chloro-2-(hydroxymethyl)-N-alkyl-arylsulfonamides as γ-secretase inhibitors
- Author
-
Kevin M. Felsenstein, Joanne J. Bronson, C.V.C. Prasad, Graham Johnson, Donna M. Barten, Michael F. Parker, Jason A. Corsa, Jeremy Mock, Valerie Guss, David W. Smith, Charles P. Sloan, Williams Andrew, Owen Brendan Wallace, Steven Hansel, Craig Polson, Keavy Daniel J, Milind Deshpande, Bergstrom Carl P, Henry H. Wang, Wai Y. Lau, and Ming Zheng
- Subjects
Stereochemistry ,Clinical Biochemistry ,Pharmaceutical Science ,Mice, Transgenic ,Biochemistry ,Chemical synthesis ,Mice ,chemistry.chemical_compound ,In vivo ,Drug Discovery ,Animals ,Hydroxymethyl ,Molecular Biology ,Alkyl ,chemistry.chemical_classification ,Sulfonamides ,Amyloid beta-Peptides ,Molecular Structure ,biology ,Chemistry ,Organic Chemistry ,Brain ,Biological activity ,Sulfonamide ,Enzyme inhibitor ,biology.protein ,Molecular Medicine ,Amyloid Precursor Protein Secretases ,Amyloid precursor protein secretase ,Protein Binding - Abstract
A series of N-alkylbenzenesulfonamides were developed from a high throughput screening hit. Classic and parallel synthesis strategies were employed to produce compounds with good in vitro and in vivo gamma-secretase activity.
- Published
- 2007
48. Discovery of D1 Dopamine Receptor Positive Allosteric Modulators: Characterization of Pharmacology and Identification of Residues that Regulate Species Selectivity
- Author
-
Michael R. Weed, Jeffrey M. Brown, Brett R. Beno, Ryan S. Westphal, Robert G. Gentles, John Watson, Yan Kong, Lisa Hunihan, Martin A. Lewis, Mary Ellen Cvijic, John E. Macor, Joanne J. Bronson, Meredith Ferrante, Thaddeus F. Molski, Ronald J. Knox, Andrew Alt, Angela Cacace, Kristin L. Rockwell, Shuanghua Hu, Adam Hendricson, and Yazhong Huang
- Subjects
Agonist ,Allosteric modulator ,Stereochemistry ,medicine.drug_class ,Allosteric regulation ,CHO Cells ,Pharmacology ,Biology ,Cell Line ,Mice ,Cricetulus ,Allosteric Regulation ,Dopamine ,Dopamine receptor D2 ,medicine ,Animals ,Humans ,Receptor ,Cells, Cultured ,chemistry.chemical_classification ,Receptors, Dopamine D2 ,Receptors, Dopamine D1 ,Amino acid ,Rats ,HEK293 Cells ,chemistry ,Biochemistry ,Dopamine receptor ,Schizophrenia ,Molecular Medicine ,medicine.drug - Abstract
The present studies represent the first published report of a dopamine D1 positive allosteric modulator (PAM). D1 receptors have been proposed as a therapeutic target for the treatment of cognitive deficits associated with schizophrenia. However, the clinical utility of orthosteric agonist compounds is limited by cardiovascular side effects, poor pharmacokinetics, lack of D1 selectivity, and an inverted dose response. A number of these challenges may be overcome by utilization of a selective D1 PAM. The current studies describe two chemically distinct D1 PAMs: Compound A [1-((rel-1S,3R,6R)-6-(benzo[d][1,3]dioxol-5-yl)bicyclo[4.1.0]heptan-3-yl)-4-(2-bromo-5-chlorobenzyl)piperazine] and Compound B [rel-(9R,10R,12S)-N-(2,6-dichloro-3-methylphenyl)-12-methyl-9,10-dihydro-9,10-ethanoanthracene-12-carboxamide]. Compound A shows pure PAM activity, with an EC50 of 230 nM and agonist activity at the D2 receptor in D2-expressing human embryonic kidney cells. Compound B shows superior potency (EC50 of 43 nM) and selectivity for D1 versus D2 dopamine receptors. Unlike Compound A, Compound B is selective for human and nonhuman primate D1 receptors, but lacks activity at the rodent (rat and mouse) D1 receptors. Using molecular biology techniques, a single amino acid was identified at position 130, which mediates the species selectivity of Compound B. These data represent the first described D1-selective PAMs and define critical amino acids that regulate species selectivity.
- Published
- 2015
49. Synthesis and antibacterial activity of nocathiacin I analogues
- Author
-
B. Narasimhulu Naidu, Kin Sing Lam, Yasutsugu Ueda, Wenying Li, Joanne J. Bronson, Hyekyung Yang, John D. Matiskella, Michael J. Pucci, Yunhui Zhang, Margaret E. Sorenson, Timothy P. Connolly, and Justin B. Sausker
- Subjects
Staphylococcus aureus ,Carboxylic acid ,Clinical Biochemistry ,Pharmaceutical Science ,Microbial Sensitivity Tests ,In Vitro Techniques ,Biochemistry ,Chemical synthesis ,Structure-Activity Relationship ,chemistry.chemical_compound ,Dehydroalanine ,Enzymatic hydrolysis ,Amide ,Drug Discovery ,Nocathiacin I ,Enterococcus faecalis ,Organic chemistry ,Molecular Biology ,Antibacterial agent ,chemistry.chemical_classification ,Molecular Structure ,Organic Chemistry ,Water ,Stereoisomerism ,Anti-Bacterial Agents ,Streptococcus pneumoniae ,Solubility ,chemistry ,Intercellular Signaling Peptides and Proteins ,Molecular Medicine ,Peptides ,Antibacterial activity - Abstract
Stereoselective reduction of dehydroalanine double bond in nocathiacin I afforded the primary amide 2. Enzymatic hydrolysis of the amide 2 provided the carboxylic acid 3, which upon coupling with a variety of amines furnished amides 4-32. Some of these semi-synthetic derivatives have retained very good antibacterial activity and have improved aqueous solubility.
- Published
- 2006
50. Synthesis and antibacterial activity of dihydro-1,2-oxazine and 2-pyrazoline oxazolidinones: novel analogs of linezolid
- Author
-
Hyekyung Yang, Joanne J. Bronson, Joan Fung-Tomc, Stan V. D'Andrea, Zhizhen Barbara Zheng, Kenneth DenBleyker, Dennis Taylor, and Junius M. Clark
- Subjects
Stereochemistry ,Clinical Biochemistry ,Pharmaceutical Science ,Pyrazoline ,Microbial Sensitivity Tests ,Gram-Positive Bacteria ,Biochemistry ,Chemical synthesis ,Mice ,chemistry.chemical_compound ,Morpholine ,Acetamides ,Drug Discovery ,Eperezolid ,Animals ,Oxazoles ,Molecular Biology ,Oxazolidinones ,Antibacterial agent ,Organic Chemistry ,Linezolid ,Anti-Bacterial Agents ,Pyrazolidine ,chemistry ,Molecular Medicine ,Antibacterial activity - Abstract
The synthesis and antibacterial activity of oxazolidinones containing dihydro-1,2-oxazine and 2-pyrazoline ring systems are described. Linezolid analogs utilizing dihydro-1,2-oxazines as morpholine mimics were prepared utilizing a nitrosoamine/diene 4+2 cycloaddition strategy. Pyrazolidine, hexahydro-pyridazine, and 2-pyrazoline analogs more closely related to eperezolid were also prepared. The most active of these new oxazolidinones were the dihydro-1,2-oxazine 6 and the 2-pyrazoline 20 both of which had potency similar to linezolid against a panel of Gram-positive bacteria.
- Published
- 2005
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