71 results on '"Anna L. Blobaum"'
Search Results
2. Discovery of VU6015929: A Selective Discoidin Domain Receptor 1/2 (DDR1/2) Inhibitor to Explore the Role of DDR1 in Antifibrotic Therapy
- Author
-
Daniel E. Jeffries, Anna L. Blobaum, Ambra Pozzi, Craig W. Lindsley, and Corina M. Borza
- Subjects
DDR1 ,010405 organic chemistry ,Chemistry ,Organic Chemistry ,Pharmacology ,01 natural sciences ,Biochemistry ,In vitro ,0104 chemical sciences ,010404 medicinal & biomolecular chemistry ,Drug Discovery ,Tyrosine Receptor Kinase ,Kinome ,Receptor ,Cytotoxicity ,Discoidin domain ,In vivo pharmacokinetics - Abstract
[Image: see text] Herein, we report the discovery of a potent and selective dual DDR1/2 inhibitor, 7e (VU6015929), displaying low cytotoxicity, good kinome selectivity, and possessing an acceptable in vitro DMPK profile with good rodent in vivo pharmacokinetics. VU6015929 potently blocks collagen-induced DDR1 activation and collagen-IV production, suggesting DDR1 inhibition as an exciting target for antifibrotic therapy.
- Published
- 2019
3. Discovery of a potent M5 antagonist with improved clearance profile. Part 2: Pyrrolidine amide-based antagonists
- Author
-
Douglas L. Orsi, Andrew S. Felts, Alice L. Rodriguez, Paige N. Vinson, Hyekyung P. Cho, Sichen Chang, Anna L. Blobaum, Colleen M. Niswender, P. Jeffrey Conn, Carrie K. Jones, Craig W. Lindsley, and Changho Han
- Subjects
Organic Chemistry ,Clinical Biochemistry ,Drug Discovery ,Pharmaceutical Science ,Molecular Medicine ,Molecular Biology ,Biochemistry - Published
- 2022
4. Discovery of a potent M5 antagonist with improved clearance profile. Part 1: Piperidine amide-based antagonists
- Author
-
Rory A. Capstick, David Whomble, Douglas L. Orsi, Andrew S. Felts, Alice L. Rodriguez, Paige N. Vinson, Sichen Chang, Anna L. Blobaum, Colleen M. Niswender, P. Jeffrey Conn, Carrie K. Jones, Craig W. Lindsley, and Changho Han
- Subjects
Organic Chemistry ,Clinical Biochemistry ,Drug Discovery ,Pharmaceutical Science ,Molecular Medicine ,Molecular Biology ,Biochemistry - Published
- 2022
5. Development and profiling of mGlu7 NAMs with a range of saturable inhibition of agonist responses in vitro
- Author
-
Carson W. Reed, Alice L. Rodriguez, Jacob J. Kalbfleisch, Mabel Seto, Matthew T. Jenkins, Anna L. Blobaum, Sichen Chang, Craig W. Lindsley, and Colleen M. Niswender
- Subjects
Organic Chemistry ,Clinical Biochemistry ,Drug Discovery ,Pharmaceutical Science ,Molecular Medicine ,Molecular Biology ,Biochemistry - Published
- 2022
6. Further exploration of an N-aryl phenoxyethoxy pyridinone-based series of mGlu3 NAMs: Challenging SAR, enantiospecific activity and in vivo efficacy
- Author
-
Kristen Gilliland, Anna L. Blobaum, Samantha E. Yohn, P. Jeffrey Conn, Craig W. Lindsley, Michael L. Schulte, Alice L. Rodriguez, Colleen M. Niswender, Mathew T. Loch, and Yousuke Yamada
- Subjects
Tail Suspension ,010405 organic chemistry ,Stereochemistry ,Aryl ,Organic Chemistry ,Clinical Biochemistry ,Pharmaceutical Science ,Selective inhibition ,01 natural sciences ,Biochemistry ,Zero maze ,0104 chemical sciences ,Marble burying ,010404 medicinal & biomolecular chemistry ,chemistry.chemical_compound ,chemistry ,In vivo ,Multidimensional optimization ,Drug Discovery ,Molecular Medicine ,G protein-coupled inwardly-rectifying potassium channel ,Molecular Biology - Abstract
This letter describes the further optimization of a series of mGlu3 NAMs based on an N-aryl phenoxyethoxy pyridinone core. A multidimensional optimization campaign, with focused matrix libraries, quickly established challenging SAR, enantiospecific activity, differences in assay read-outs (Ca2+ flux via a promiscuous G protein (Gα15) versus native coupling to GIRK channels), identified both full and partial mGlu3 NAMs and a new in vivo tool compound, VU6017587. This mGlu3 NAM showed efficacy in tail suspension, elevated zero maze and marble burying, suggesting selective inhibition of mGlu3 affords anxiolytic-like and antidepressant-like phenotypes in mice.
- Published
- 2019
7. Surveying heterocycles as amide bioisosteres within a series of mGlu7 NAMs: Discovery of VU6019278
- Author
-
Carson W. Reed, Matthew T. Jenkins, Colleen M. Niswender, Alice L. Rodriguez, P. Jeffrey Conn, Darren W. Engers, Marc C. Quitlag, Craig W. Lindsley, Jordan P Washecheck, and Anna L. Blobaum
- Subjects
010405 organic chemistry ,Stereochemistry ,Organic Chemistry ,Clinical Biochemistry ,Allosteric regulation ,Pharmaceutical Science ,Hepatic clearance ,Plasma protein binding ,Ring (chemistry) ,01 natural sciences ,Biochemistry ,0104 chemical sciences ,010404 medicinal & biomolecular chemistry ,chemistry.chemical_compound ,chemistry ,Metabotropic glutamate receptor ,Amide ,Drug Discovery ,Molecular Medicine ,Moiety ,Bioisostere ,Molecular Biology - Abstract
This letter describes a diversity-oriented library approach to rapidly assess diverse heterocycles as bioisosteric replacements for a metabolically labile amide moiety within a series of mGlu7 negative allosteric modulators (NAMs). SAR rapidly honed in on either a 1,2,4- or 1,3,4-oxadizaole ring system as an effective bioisostere for the amide. Further optimization of the southern region of the mGlu7 NAM chemotype led to the discovery of VU6019278, a potent mGlu7 NAM (IC50 = 501 nM, 6.3% L-AP4 Min) with favorable plasma protein binding (rat fu = 0.10), low predicted hepatic clearance (rat CLhep = 27.7 mL/min/kg) and high CNS penetration (rat Kp = 4.9, Kp,uu = 0.65).
- Published
- 2019
8. The discovery of VU0652957 (VU2957, Valiglurax): SAR and DMPK challenges en route to an mGlu4 PAM development candidate
- Author
-
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
- Subjects
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).
- Published
- 2019
9. Discovery of 4-alkoxy-6-methylpicolinamide negative allosteric modulators of metabotropic glutamate receptor subtype 5
- Author
-
J. Scott Daniels, Christopher J. Brassard, Ryan D. Morrison, Alice L. Rodriguez, Anna L. Blobaum, Kyle A. Emmitte, Andrew S. Felts, P. Jeffrey Conn, Colleen M. Niswender, Carrie K. Jones, Katrina A. Bollinger, and Craig W. Lindsley
- Subjects
Pyrimidine ,Stereochemistry ,Receptor, Metabotropic Glutamate 5 ,Metabolite ,Clinical Biochemistry ,Allosteric regulation ,Pharmaceutical Science ,Ligands ,01 natural sciences ,Biochemistry ,Article ,Structure-Activity Relationship ,chemistry.chemical_compound ,Allosteric Regulation ,Drug Discovery ,Animals ,Humans ,Moiety ,Picolinic Acids ,Molecular Biology ,Aldehyde oxidase ,Dose-Response Relationship, Drug ,Molecular Structure ,010405 organic chemistry ,Chemistry ,Organic Chemistry ,Ligand (biochemistry) ,Rats ,0104 chemical sciences ,010404 medicinal & biomolecular chemistry ,Metabotropic glutamate receptor ,Molecular Medicine ,Pharmacophore - Abstract
This letter describes the further chemical optimization of VU0424238 (auglurant), an mGlu5 NAM clinical candidate that failed in non-human primate (NHP) 28 day toxicology due to accumulation of a species-specific aldehyde oxidase (AO) metabolite of the pyrimidine head group. Here, we excised the pyrimidine moiety, identified the minimum pharmacophore, and then developed a new series of saturated ether head groups that ablated any AO contribution to metabolism. Putative back-up compounds in this novel series provided increased sp3 character, uniform CYP450-mediated metabolism across species, good functional potency and high CNS penetration. Key to the optimization was a combination of matrix and iterative libraries that allowed rapid surveillance of multiple domains of the allosteric ligand.
- Published
- 2019
10. Isoform selective PLD inhibition by novel, chiral 2,8-diazaspiro[4.5]decan-1-one derivatives
- Author
-
Alex G. Waterson, H. Alex Brown, Anna L. Blobaum, Nathan R. Kett, Sarah A. Scott, and Craig W. Lindsley
- Subjects
0301 basic medicine ,Gene isoform ,Clinical Biochemistry ,Pharmaceutical Science ,Biochemistry ,Inhibitory Concentration 50 ,Structure-Activity Relationship ,03 medical and health sciences ,In vivo ,Drug Discovery ,Phospholipase D ,Animals ,Humans ,Protein Isoforms ,Spiro Compounds ,Enzyme Inhibitors ,Molecular Biology ,Chemistry ,Organic Chemistry ,Phosphodiesterase ,Stereoisomerism ,Highly selective ,Combinatorial chemistry ,Small molecule ,Rats ,HEK293 Cells ,030104 developmental biology ,Free fraction ,Molecular Medicine ,Half-Life - Abstract
This letter describes the on-going SAR efforts to develop PLD1, PLD2 and dual PLD1/2 inhibitors with improved physiochemical and disposition properties as well as securing intellectual property position. Previous PLD inhibitors, based on a triazaspiro[4.5]decanone core proved to be highly selective PLD2 inhibitors, but with low plasma free fraction (rat, human fu 65 mL/min/kg) and very short half-lives in vivo (t1/2 3 h), and led to the first issued US patent claiming composition of matter for small molecule PLD inhibitors.
- Published
- 2018
11. Discovery of VU2957 (Valiglurax): An mGlu4 Positive Allosteric Modulator Evaluated as a Preclinical Candidate for the Treatment of Parkinson’s Disease
- Author
-
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
- Subjects
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.
- Published
- 2018
12. Discovery, synthesis and characterization of a series of 7-aryl-imidazo[1,2-a]pyridine-3-ylquinolines as activin-like kinase (ALK) inhibitors
- Author
-
Anna L. Blobaum, Anish K. Vadukoot, Charles H. Williams, Corey R. Hopkins, Andrew S. Felts, Darren W. Engers, Sean R. Bollinger, Craig W. Lindsley, and Charles C. Hong
- Subjects
Pyridines ,Clinical Biochemistry ,Pharmaceutical Science ,01 natural sciences ,Biochemistry ,Article ,chemistry.chemical_compound ,Structure-Activity Relationship ,In vivo ,Skeletal disease ,Pyridine ,Drug Discovery ,medicine ,Animals ,Humans ,Child ,Imidazolines ,Molecular Biology ,Protein Kinase Inhibitors ,010405 organic chemistry ,Kinase ,Aryl ,Organic Chemistry ,Diffuse Intrinsic Pontine Glioma ,medicine.disease ,Pediatric cancer ,0104 chemical sciences ,Rats ,010404 medicinal & biomolecular chemistry ,chemistry ,Myositis Ossificans ,Fibrodysplasia ossificans progressiva ,Mutation ,Cancer research ,Microsomes, Liver ,Quinolines ,Molecular Medicine ,Activin Receptors, Type I ,Signal Transduction - Abstract
The activin-like kinases are a family of kinases that play important roles in a variety of disease states. Of this class of kinases, ALK2, has been shown by a gain-of-function to be the primary driver of the childhood skeletal disease fibrodysplasia ossificans progressiva (FOP) and more recently the pediatric cancer diffuse intrinsic pontine glioma (DIPG). Herein, we report our efforts to identify a novel imidazo[1,2-a]pyridine scaffold as potent inhibitors of ALK2 with good in vivo pharmacokinetic properties suitable for future animal studies.
- Published
- 2020
13. VU6007477, a Novel M1 PAM Based on a Pyrrolo[2,3-b]pyridine Carboxamide Core Devoid of Cholinergic Adverse Events
- Author
-
Anna L. Blobaum, Jerri M. Rook, Jonathan W. Dickerson, Colleen M. Niswender, Julie L. Engers, Hekyung P Cho, Elizabeth S. Childress, Darren W. Engers, Rory A. Capstick, P. Jeffrey Conn, Craig W. Lindsley, Vincent B. Luscombe, and Madeline F. Long
- Subjects
0301 basic medicine ,Agonist ,medicine.drug_class ,Organic Chemistry ,Allosteric regulation ,Carboxamide ,Pharmacology ,Biochemistry ,03 medical and health sciences ,chemistry.chemical_compound ,030104 developmental biology ,0302 clinical medicine ,chemistry ,Drug Discovery ,Pyridine ,Toxicity ,medicine ,Potency ,Cholinergic ,030217 neurology & neurosurgery ,EC50 - Abstract
[Image: see text] Herein, we report the chemical optimization of a new series of M(1) positive allosteric modulators (PAMs) based on a novel pyrrolo[2,3-b]pyridine core, developed via scaffold hopping and iterative parallel synthesis. The vast majority of analogs in this series proved to display robust cholinergic seizure activity. However, by removal of the secondary hydroxyl group, VU6007477 resulted with good rat M(1) PAM potency (EC(50) = 230 nM, 93% ACh max), minimal M(1) agonist activity (agonist EC(50) > 10 μM), good CNS penetration (rat brain/plasma K(p) = 0.28, K(p,uu) = 0.32; mouse K(p) = 0.16, K(p,uu) = 0.18), and no cholinergic adverse events (AEs, e.g., seizures). This work demonstrates that within a chemical series prone to robust M(1) ago-PAM activity, SAR can result, which affords pure M(1) PAMs, devoid of cholinergic toxicity/seizure liability.
- Published
- 2018
14. 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
- Author
-
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
- Subjects
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).
- Published
- 2018
15. The discovery of VU0486846: steep SAR from a series of M1 PAMs based on a novel benzomorpholine core
- Author
-
Anna L. Blobaum, Jeanette L. Bertron, Jerri M. Rook, Kellie D. Nance, Colleen M. Niswender, Darren W. Engers, Pedro M. Garcia-Barrantes, P. Jeffrey Conn, James M. Salovich, Joseph D. Panarese, Craig W. Lindsley, Shaun R. Stauffer, and Hyekyung P. Cho
- Subjects
0301 basic medicine ,Allosteric modulator ,Chemistry ,Organic Chemistry ,Clinical Biochemistry ,Pharmaceutical Science ,Computational biology ,Biochemistry ,Cns penetration ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,030220 oncology & carcinogenesis ,Drug Discovery ,Molecular Medicine ,Molecular Biology - Abstract
This letter describes the chemical optimization of a new series of M1 positive allosteric modulators (PAMs) based on a novel benzomorpholine core, developed via iterative parallel synthesis, and culminating in the highly utilized rodent in vivo tool compound, VU0486846 (7), devoid of adverse effect liability. This is the first report of the optimization campaign (SAR and DMPK profiling) that led to the discovery of VU0486846 and details all of the challenges faced in allosteric modulator programs (both steep and flat SAR, as well as subtle structural changes affecting CNS penetration and overall physiochemical and DMPK properties).
- Published
- 2018
16. Discovery of 6-(pyrimidin-5-ylmethyl)quinoline-8-carboxamide negative allosteric modulators of metabotropic glutamate receptor subtype 5
- Author
-
Alice L. Rodriguez, Anna L. Blobaum, Frank W. Byers, Ryan D. Morrison, P. Jeffrey Conn, Colleen M. Niswender, J. Scott Daniels, Craig W. Lindsley, Kyle A. Emmitte, and Andrew S. Felts
- Subjects
Male ,0301 basic medicine ,Stereochemistry ,medicine.drug_class ,Receptor, Metabotropic Glutamate 5 ,Clinical Biochemistry ,Allosteric regulation ,Pharmaceutical Science ,Carboxamide ,030226 pharmacology & pharmacy ,Biochemistry ,Article ,Rats, Sprague-Dawley ,Structure-Activity Relationship ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Allosteric Regulation ,Drug Discovery ,medicine ,Animals ,Humans ,Receptor ,Molecular Biology ,Diaryl ether ,Dose-Response Relationship, Drug ,Molecular Structure ,Chemistry ,Organic Chemistry ,Quinoline ,Metabolism ,Metabolic stability ,Rats ,Pyrimidines ,030104 developmental biology ,Metabotropic glutamate receptor ,Quinolines ,Molecular Medicine - Abstract
Based on previous work that established fused heterocycles as viable alternatives for the picolinamide core of our lead series of mGlu(5) negative allosteric modulators (NAMs), we designed a novel series of 6-(pyrimidin-5-ylmethyl)quinoline-8-carboxamide mGlu(5) NAMs. These new quinoline derivatives also contained carbon linkers as replacements for the diaryl ether oxygen atom common to our previously published chemotypes. Compounds were evaluated in a cell-based functional mGlu(5) assay, and an exemplar analog 27 was more than 60-fold selective versus the other seven mGlu receptors. Selected compounds were also studied in metabolic stability assays in rat and human S9 hepatic fractions and exhibited a mixture of P450- and non-P450-mediated metabolism.
- Published
- 2018
17. A Novel M1 PAM VU0486846 Exerts Efficacy in Cognition Models without Displaying Agonist Activity or Cholinergic Toxicity
- Author
-
Jonathan W. Dickerson, Anna L. Blobaum, Jerri M. Rook, Kellie D. Nance, Colleen M. Niswender, Shaun R. Stauffer, Craig W. Lindsley, Joel M. Harp, Hyekyung P. Cho, Sean P. Moran, James Maksymetz, Pedro M. Garcia-Barrantes, P. Jeffrey Conn, Carrie K. Jones, Daniel H. Remke, Jeanette L. Bertron, and Sichen Chang
- Subjects
0301 basic medicine ,Agonist ,Physiology ,medicine.drug_class ,Morpholines ,Cognitive Neuroscience ,Allosteric regulation ,Prefrontal Cortex ,CHO Cells ,Biochemistry ,Article ,Mice ,03 medical and health sciences ,Cognition ,Cricetulus ,0302 clinical medicine ,Allosteric Regulation ,Seizures ,Conditioning, Psychological ,Muscarinic acetylcholine receptor ,medicine ,Animals ,Cognitive Dysfunction ,Prefrontal cortex ,Receptor ,Chemistry ,Antagonist ,Fear ,Cell Biology ,General Medicine ,Risperidone ,Rats ,030104 developmental biology ,Exploratory Behavior ,Pyrazoles ,Cholinergic ,Neuroscience ,030217 neurology & neurosurgery ,Acetylcholine ,Antipsychotic Agents ,medicine.drug - Abstract
Selective activation of the M(1) subtype of muscarinic acetylcholine receptor, via positive allosteric modulation (PAM), is an exciting strategy to improve cognition in schizophrenia and Alzheimer’s disease patients. However, highly potent M(1) ago-PAMs, such as MK-7622, PF-06764427, and PF-06827443, can engender excessive activation of M(1), leading to agonist actions in the prefrontal cortex (PFC) that impair cognitive function, induce behavioral convulsions, and result in other classic cholinergic adverse events (AEs). Here, we report a fundamentally new and highly selective M(1) PAM, VU0486846. VU0486846 possesses only weak agonist activity in M(1)-expressing cell lines with high receptor reserve and is devoid of agonist actions in the PFC, unlike previously reported ago-PAMs MK-7622, PF-06764427, and PF-06827443. Moreover, VU0486846 shows no interaction with antagonist binding at the orthosteric acetylcholine (ACh) site (e.g., neither bitopic nor displaying negative cooperativity with [(3)H]-NMS binding at the orthosteric site), no seizure liability at high brain exposures, and no cholinergic AEs. However, as opposed to ago-PAMs, VU0486846 produces robust efficacy in the novel object recognition model of cognitive function. Importantly, we show for the first time that an M(1) PAM can reverse the cognitive deficits induced by atypical antipsychotics, such as risperidone. These findings further strengthen the argument that compounds with modest in vitro M(1) PAM activity (EC(50) > 100 nM) and pure-PAM activity in native tissues display robust procognitive efficacy without AEs mediated by excessive activation of M(1). Overall, the combination of compound assessment with recombinant in vitro assays (mindful of receptor reserve), native tissue systems (PFC), and phenotypic screens (behavioral convulsions) is essential to fully understand and evaluate lead compounds and enhance success in clinical development.
- Published
- 2018
18. Discovery of a novel class of heteroaryl-pyrrolidinones as positive allosteric modulators of the muscarinic acetylcholine receptor M1
- Author
-
Paul K. Spearing, Colleen M. Niswender, Hyekyung P. Cho, Anna L. Blobaum, P. Jeffrey Conn, Alice L. Rodriguez, Aaron M. Bender, Vincent B. Luscombe, Craig W. Lindsley, Olivier Boutaud, and Darren W. Engers
- Subjects
010405 organic chemistry ,Chemistry ,Stereochemistry ,Organic Chemistry ,Clinical Biochemistry ,Allosteric regulation ,Pharmaceutical Science ,Muscarinic acetylcholine receptor M1 ,01 natural sciences ,Biochemistry ,In vitro ,0104 chemical sciences ,010404 medicinal & biomolecular chemistry ,Drug Discovery ,Muscarinic acetylcholine receptor ,Molecular Medicine ,Structure–activity relationship ,Pyrrolidinones ,Molecular Biology - Abstract
This Letter describes the synthesis and optimization of a series of heteroaryl-pyrrolidinone positive allosteric modulators (PAMs) of the muscarinic acetylcholine receptor M1 (mAChR M1). Through the continued optimization of M1 PAM tool compound VU0453595, with a focus on replacement of the 6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one with a wide variety of alternative 4,5-dihydropyrrolo-fused heteroaromatics, the generation of M1 PAMs with structurally novel chemotypes is disclosed. Two compounds from these subseries, 8b (VU6005610) and 20a (VU6005852), show robust selectivity for the M1 mAChR, and no M1 agonism. Both compounds have favorable preliminary PK profiles in vitro;8b additionally demonstrates high brain exposure in a rodent IV cassette model.
- Published
- 2021
19. Discovery and optimization of a novel CNS penetrant series of mGlu4 PAMs based on a 1,4-thiazepane core with in vivo efficacy in a preclinical Parkinsonian model
- Author
-
Kaylee J. Stillwell, Jonathan W. Dickerson, Matthew T. Loch, Craig W. Lindsley, Mark G. Fulton, Olivier Boutaud, P. Jeffrey Conn, Colleen M. Niswender, Caitlin N. Kent, Alice L. Rodriguez, Jerri L. Rook, and Anna L. Blobaum
- Subjects
010405 organic chemistry ,Chemistry ,Organic Chemistry ,Clinical Biochemistry ,Pharmaceutical Science ,Pharmacology ,Catalepsy ,medicine.disease ,01 natural sciences ,Biochemistry ,0104 chemical sciences ,Cns penetration ,010404 medicinal & biomolecular chemistry ,chemistry.chemical_compound ,In vivo ,Drug Discovery ,medicine ,Molecular Medicine ,Penetrant (biochemical) ,Molecular Biology - Abstract
A high throughput screen (HTS) identified a novel, but weak (EC50 = 6.2 μM, 97% Glu Max) mGlu4 PAM chemotype based on a 1,4-thiazepane core, VU0544412. Reaction development and chemical optimization delivered a potent mGlu4 PAM VU6022296 (EC50 = 32.8 nM, 108% Glu Max) with good CNS penetration (Kp = 0.45, Kp,uu = 0.70) and enantiopreference. Finally, VU6022296 displayed robust, dose-dependent efficacy in reversing Haloperidol-Induced Catalepsy (HIC), a rodent preclinical Parkinson’s disease model.
- Published
- 2021
20. Species-Specific Involvement of Aldehyde Oxidase and Xanthine Oxidase in the Metabolism of the Pyrimidine-Containing mGlu5-Negative Allosteric Modulator VU0424238 (Auglurant)
- Author
-
Rachel D. Crouch, Anna L. Blobaum, Andrew S. Felts, P. Jeffrey Conn, and Craig W. Lindsley
- Subjects
Pharmacology ,chemistry.chemical_classification ,Allosteric modulator ,Metabolite ,Pharmaceutical Science ,Allopurinol ,Metabolism ,Biology ,030226 pharmacology & pharmacy ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Enzyme ,chemistry ,Biochemistry ,Metabotropic glutamate receptor ,030220 oncology & carcinogenesis ,medicine ,Xanthine oxidase ,Aldehyde oxidase ,medicine.drug - Abstract
Aldehyde oxidase (AO) and xanthine oxidase (XO) are molybdo-flavoenzymes that catalyze oxidation of aromatic azaheterocycles. Differences in AO activity have been reported among various species, including rats, humans, and monkeys. Herein we report a species difference in the enzymes responsible for the metabolism of the negative allosteric modulator of metabotropic glutamate receptor subtype 5 (mGlu5 NAM) VU0424238 (VU238, auglurant). Hepatic S9 incubations with AO and XO specific inhibitors hydralazine and allopurinol indicated that rats and cynomolgus monkeys both oxidized VU238 to the 6-oxopyrimidine metabolite M1 via an AO-mediated pathway, whereas secondary oxidation to the 2,6-dioxopyrimidine metabolite M2 was mediated predominantly by AO in monkeys and XO in rats. Despite differences in enzymatic pathways, intrinsic clearance (CLint) of M1 was similar between species (cynomolgus and rat CLint = 2.00 ± 0.040 and 2.19 ± 0.201 μl/min per milligram of protein, respectively). Inhibitor studies in the S9 of multiple species indicated that oxidation of VU238 to M1 was mediated predominantly by AO in humans, cynomolgus and rhesus monkeys, rats, mice, guinea pigs, and minipigs. Oxidation of M1 to M2 was mediated predominantly by XO in rats and mice and by AO in monkeys and guinea pigs, whereas low turnover prevented enzyme phenotyping in humans and minipigs. Additionally, inhibitor experiments indicated that oxidation at the 2-position of the pyrimidine ring of the known AO substrate, BIBX1382, was mediated by AO in all species, although production of this metabolite was comparatively low in rats and mice. These data may suggest low reactivity of rat AO toward 2-oxidation of pyrimidine-containing compounds and highlight the importance of thoroughly characterizing AO-metabolized drug candidates in multiple preclinical species.
- Published
- 2017
21. Discovery of VU6005649, a CNS Penetrant mGlu7/8 Receptor PAM Derived from a Series of Pyrazolo[1,5-a]pyrimidines
- Author
-
Vincent B. Luscombe, Sichen Chang, Michael Bubser, Craig W. Lindsley, Joel M. Harp, Eileen M. Engelberg, Colleen M. Niswender, Darren W. Engers, P. Jeffrey Conn, Carrie K. Jones, Katrina A. Bollinger, Alice L. Rodriguez, Mabel Seto, Anna L. Blobaum, Rocco G. Gogliotti, Matthew T. Loch, and Masahito Abe
- Subjects
0301 basic medicine ,Pyrimidine ,Chemistry ,Stereochemistry ,Organic Chemistry ,Contextual fear ,Biochemistry ,Cns penetration ,Receptor selectivity ,03 medical and health sciences ,chemistry.chemical_compound ,030104 developmental biology ,0302 clinical medicine ,In vivo ,Drug Discovery ,Receptor ,030217 neurology & neurosurgery - Abstract
Herein, we report the structure–activity relationships within a series of mGlu7 PAMs based on a pyrazolo[1,5-a]pyrimidine core with excellent CNS penetration (Kps > 1 and Kp,uus > 1). Analogues in this series proved to display a range of Group III mGlu receptor selectivity, but VU6005649 emerged as the first dual mGlu7/8 PAM, filling a void in the Group III mGlu receptor PAM toolbox and demonstrating in vivo efficacy in a mouse contextual fear conditioning model.
- Published
- 2017
22. Development and kilogram-scale synthesis of mGlu5 negative allosteric modulator VU0424238 (auglurant)
- Author
-
Nayak K. Prashanth, Devendrareddy Pallalu, Anna L. Blobaum, P. Jeffrey Conn, M. Rajendraswami, Kyle A. Emmitte, Craig W. Lindsley, Thomas K. David, Carrie K. Jones, Arlindo L. Castelhano, and Michael J. Kates
- Subjects
0301 basic medicine ,Allosteric modulator ,Organic Chemistry ,Biochemistry ,Alternative treatment ,03 medical and health sciences ,chemistry.chemical_compound ,030104 developmental biology ,0302 clinical medicine ,chemistry ,Nucleophilic aromatic substitution ,Drug Discovery ,Pyridine ,Organic chemistry ,030217 neurology & neurosurgery - Abstract
This communication details the kilogram-scale synthesis of N-(5-fluoropyridin-2-yl)-6-methyl-4-(pyrimidin-5-yloxy)picolinamide (VU0424238, auglurant), a novel mGlu5 negative allosteric modulator (NAM) developed as an alternative treatment for depression. The process highlights a challenging pyridine N-oxidation sequence, an SNAr reaction, and the elimination of all chromatography steps (required in the medicinal chemistry route) with replacement by highly efficient recrystallizations (save one silica plug). The improved process was utilized for the preparation of a 1.2 kg toxicology batch, as well as a 2.82 kg GMP batch to support the Phase I trial, in very high purity (99.8%).
- Published
- 2017
23. Design and Synthesis of mGlu2 NAMs with Improved Potency and CNS Penetration Based on a Truncated Picolinamide Core
- Author
-
Rebecca L. Weiner, Katrina A. Bollinger, Christopher J. Brassard, Hyekyung P. Cho, Julie L. Engers, Kyle A. Emmitte, Andrew S. Felts, Carrie K. Jones, Alice L. Rodriguez, Anna L. Blobaum, Craig W. Lindsley, P. Jeffrey Conn, Michael Bubser, Sichen Chang, and Colleen M. Niswender
- Subjects
0301 basic medicine ,Allosteric modulator ,Chemistry ,Stereochemistry ,Organic Chemistry ,Penetration (firestop) ,Biochemistry ,Cns penetration ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Drug Discovery ,Potency ,Pet tracer ,030217 neurology & neurosurgery - Abstract
Herein, we detail the optimization of the mGlu2 negative allosteric modulator (NAM), VU6001192, by a reductionist approach to afford a novel, simplified mGlu2 NAM scaffold. This new chemotype not only affords potent and selective mGlu2 inhibition, as exemplified by VU6001966 (mGlu2 IC50 = 78 nM, mGlu3 IC50 > 30 μM), but also excellent central nervous system (CNS) penetration (Kp = 1.9, Kp,uu = 0.78), a feature devoid in all previously disclosed mGlu2 NAMs (Kps ≈ 0.3, Kp,uus ≈ 0.1). Moreover, this series, based on overall properties, represents an exciting lead series for potential mGlu2 PET tracer development.
- Published
- 2017
24. Discovery of a Novel Series of Orally Bioavailable and CNS Penetrant Glucagon-like Peptide-1 Receptor (GLP-1R) Noncompetitive Antagonists Based on a 1,3-Disubstituted-7-aryl-5,5-bis(trifluoromethyl)-5,8-dihydropyrimido[4,5-d]pyrimidine-2,4(1H,3H)-dione Core
- Author
-
Hyekyung P. Cho, Anna L. Blobaum, Kellie D. Nance, Colleen M. Niswender, Craig W. Lindsley, Tiffany D. Farmer, Emily Days, C. David Weaver, Anastasia G. Coldren, and Kevin D. Niswender
- Subjects
0301 basic medicine ,endocrine system ,Trifluoromethyl ,Pyrimidine ,Insulin ,medicine.medical_treatment ,digestive, oral, and skin physiology ,Antagonist ,Pharmacology ,Glucagon-like peptide-1 ,03 medical and health sciences ,chemistry.chemical_compound ,030104 developmental biology ,Biochemistry ,chemistry ,In vivo ,Drug Discovery ,medicine ,Molecular Medicine ,Receptor ,Penetrant (biochemical) ,hormones, hormone substitutes, and hormone antagonists - Abstract
A duplexed, functional multiaddition high throughput screen and subsequent optimization effort identified the first orally bioavailable and CNS penetrant glucagon-like peptide-1 receptor (GLP-1R) noncompetitive antagonist. Antagonist 5d not only blocked exendin-4-stimulated insulin release in islets but also lowered insulin levels while increasing blood glucose in vivo.
- Published
- 2017
25. Discovery of VU0467485/AZ13713945: An M4 PAM Evaluated as a Preclinical Candidate for the Treatment of Schizophrenia
- Author
-
Mark E. Duggan, Michael W. Wood, Michael R. Wood, Craig W. Lindsley, Vincent B. Luscombe, Miguel A. Hurtado, Bruce J. Melancon, Alice L. Rodriguez, Thomas M. Bridges, Atin Lamsal, Michael Bubser, Anna L. Blobaum, Carrie K. Jones, Meredith J. Noetzel, Darren W. Engers, Sichen Chang, Michael S. Poslusney, P. Jeffrey Conn, Rebecca L. Weiner, Nicholas J. Brandon, Kellie D. Nance, and Colleen M. Niswender
- Subjects
0301 basic medicine ,Chemistry ,Organic Chemistry ,Allosteric regulation ,Pharmacology ,medicine.disease ,Biochemistry ,In vitro ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,In vivo ,Schizophrenia ,Drug Discovery ,Muscarinic acetylcholine receptor ,medicine ,Potency ,030217 neurology & neurosurgery - Abstract
Herein, we report the structure–activity relationships within a series of potent, selective, and orally bioavailable muscarinic acetylcholine receptor 4 (M4) positive allosteric modulators (PAMs). Compound 6c (VU0467485) possesses robust in vitro M4 PAM potency across species and in vivo efficacy in preclinical models of schizophrenia. Coupled with an attractive DMPK profile and suitable predicted human PK, 6c (VU0467485) was evaluated as a preclinical development candidate.
- Published
- 2016
26. Discovery, characterization and biological evaluation of a novel ( R )-4,4-difluoropiperidine scaffold as dopamine receptor 4 (D 4 R) antagonists
- Author
-
Corey R. Hopkins, Kayla J. Temple, Andrea L. McCollum, Craig W. Lindsley, Joel M. Harp, Jonathan O. Witt, Miguel A. Hurtado, Daniel E. Jeffries, and Anna L. Blobaum
- Subjects
Scaffold ,010405 organic chemistry ,Stereochemistry ,Chemistry ,Organic Chemistry ,Clinical Biochemistry ,Pharmaceutical Science ,01 natural sciences ,Biochemistry ,0104 chemical sciences ,03 medical and health sciences ,0302 clinical medicine ,Dopamine receptor ,Drug Discovery ,Molecular Medicine ,Receptor ,Molecular Biology ,030217 neurology & neurosurgery ,Biological evaluation - Abstract
Herein, we report the synthesis and structure-activity relationship of a novel series of (R)-4,4-difluoropiperidine core scaffold as dopamine receptor 4 (D4) antagonists. A series of compounds from this scaffold are highly potent against the D4 receptor and selective against the other dopamine receptors. In addition, we were able to confirm the active isomer as the (R)-enantiomer via an X-ray crystal structure.
- Published
- 2016
27. Identification of the minimum PAR4 inhibitor pharmacophore and optimization of a series of 2-methoxy-6-arylimidazo[2,1- b ][1,3,4]thiadiazoles
- Author
-
Shaun R. Stauffer, Craig W. Lindsley, Matthew T. Duvernay, Anna L. Blobaum, Heidi E. Hamm, Jae G. Maeng, and Kayla J. Temple
- Subjects
Blood Platelets ,0301 basic medicine ,Platelet Aggregation ,Stereochemistry ,Clinical Biochemistry ,Pharmaceutical Science ,Peptide ,Plasma protein binding ,Biochemistry ,Article ,03 medical and health sciences ,Non-competitive inhibition ,Thiadiazoles ,Drug Discovery ,Humans ,Molecular Biology ,chemistry.chemical_classification ,030102 biochemistry & molecular biology ,Hydrogen bond ,Organic Chemistry ,Thrombin ,Combinatorial chemistry ,030104 developmental biology ,chemistry ,High plasma ,Molecular Medicine ,Platelet aggregation inhibitor ,Receptors, Thrombin ,Pharmacophore ,Platelet Aggregation Inhibitors - Abstract
This letter describes the further deconstruction of the known PAR4 inhibitor chemotypes (MWs 490 – 525 and with high plasma protein binding) to identify a minimum PAR4 pharmacophore devoid of metabolic liabilities and improved properties. This exercise identified a greatly simplified 2-methoxy-6-arylimidazo[2,1-b][1,3,4]thiadiazole scaffold that afforded nanomolar inhibition of both activating peptide and γ-thrombin mediated PAR4 stimulation, while reducing both molecular weight and the number of hydrogen bond donors/acceptors by ~50%. This minimum PAR4 pharmacophore, with competitive inhibition, versus non-competitive of the larger chemotypes, allows an ideal starting point to incorporate desired functional groups to engender optimal DMPK properties towards a preclinical candidate.
- Published
- 2016
28. Synthesis and SAR of a series of mGlu7 NAMs based on an ethyl-8-methoxy-4-(4-phenylpiperazin-1-yl)quinoline carboxylate core
- Author
-
Craig W. Lindsley, Colleen M. Niswender, Matthew T. Jenkins, Paul K. Spearing, Jacob J. Kalbfleisch, Anna L. Blobaum, Charlotte Park, Marc C. Quitalig, P. Jeffrey Conn, Carson W. Reed, and Alice L. Rodriguez
- Subjects
Chemotype ,010405 organic chemistry ,Stereochemistry ,Organic Chemistry ,Clinical Biochemistry ,Allosteric regulation ,Quinoline ,Pharmaceutical Science ,Ethyl ester ,01 natural sciences ,Biochemistry ,0104 chemical sciences ,010404 medicinal & biomolecular chemistry ,chemistry.chemical_compound ,Piperazine ,chemistry ,Drug Discovery ,Molecular Medicine ,Moiety ,Carboxylate ,Selectivity ,Molecular Biology - Abstract
A High-Throughput Screening (HTS) campaign identified a fundamentally new mGlu7 NAM chemotype, based on an ethyl-8-methoxy-4-(4-phenylpiperazin-1-yl)quinolone carboxylate core. The initial hit, VU0226390, was a potent mGlu7 NAM (IC50 = 647 nM, 6% L-AP4 min) with selectivity versus the other group III mGlu receptors (>30 μM vs. mGlu4 and mGlu8). A multi-dimensional optimization effort surveyed all regions of this new chemotype, and found very steep SAR, reminiscent of allosteric modulators, and unexpected piperazine mimetics (whereas classical bioisosteres failed). While mGlu7 NAM potency could be improved (IC50s ~ 350 nM), the necessity of the ethyl ester moiety and poor physiochemical and DMPK properties precluded optimization towards in vivo tool compounds or clinical candidates. Still, this hit-to-lead campaign afforded key medicinal chemistry insights and new opportunities.
- Published
- 2020
29. Discovery of 3-aminopicolinamides as metabotropic glutamate receptor subtype 4 (mGlu4) positive allosteric modulator warheads engendering CNS exposure and in vivo efficacy
- Author
-
Pedro M. Garcia-Barrantes, Colleen M. Niswender, J. Scott Daniels, Corey R. Hopkins, Rocco D. Gogliotti, P. Jeffrey Conn, Carrie K. Jones, Darren W. Engers, Analisa D. Thompson, Patrick R. Gentry, Anna L. Blobaum, Ryan D. Morrison, Joseph D. Panarese, and Craig W. Lindsley
- Subjects
Central Nervous System ,0301 basic medicine ,Allosteric modulator ,Clinical Biochemistry ,Allosteric regulation ,Pharmaceutical Science ,Pharmacology ,Catalepsy ,Receptors, Metabotropic Glutamate ,Biochemistry ,Article ,Structure-Activity Relationship ,03 medical and health sciences ,0302 clinical medicine ,Allosteric Regulation ,In vivo ,Drug Discovery ,medicine ,Animals ,Humans ,Potency ,Structure–activity relationship ,Molecular Biology ,Dose-Response Relationship, Drug ,Molecular Structure ,Chemistry ,Metabotropic glutamate receptor 4 ,Organic Chemistry ,medicine.disease ,Amides ,Rats ,Disease Models, Animal ,030104 developmental biology ,Metabotropic glutamate receptor ,Picolines ,Molecular Medicine ,030217 neurology & neurosurgery - Abstract
This letter describes the further chemical optimization of the picolinamide-derived family of mGlu4 PAMs wherein we identified a 3-amino substituent to the picolinamide warhead that engendered potency, CNS penetration and in vivo efficacy. From this optimization campaign, VU0477886 emerged as a potent (EC50 = 95 nM, 89% Glu Max) mGlu4 PAM with an attractive DMPK profile (brain:plasma Kp = 1.3), rat CLp = 4.0 mL/min/kg, t1/2 = 3.7 h) and robust efficacy in our standard preclinical Parkinson's disease model, haloperidol-induced catalepsy (HIC).
- Published
- 2016
30. Synthesis and characterization of a series of chiral alkoxymethyl morpholine analogs as dopamine receptor 4 (D4R) antagonists
- Author
-
Corey R. Hopkins, Miguel A. Hurtado, Jonathan O. Witt, Kayla J. Temple, Craig W. Lindsley, Andrea L. McCollum, Daniel E. Jeffries, Eric D. Huseman, Anna L. Blobaum, and Hyekyung C. Plumley
- Subjects
medicine.drug_class ,Stereochemistry ,Morpholines ,Clinical Biochemistry ,Drug Evaluation, Preclinical ,Pharmaceutical Science ,01 natural sciences ,Biochemistry ,Article ,Structure-Activity Relationship ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Dopamine ,Morpholine ,Drug Discovery ,medicine ,Animals ,Humans ,Structure–activity relationship ,Molecular Biology ,010405 organic chemistry ,Receptors, Dopamine D4 ,Organic Chemistry ,Antagonist ,Receptor antagonist ,Rats ,0104 chemical sciences ,chemistry ,Dopamine receptor ,Microsomes, Liver ,Dopamine Antagonists ,Molecular Medicine ,Selectivity ,030217 neurology & neurosurgery ,medicine.drug - Abstract
Herein, we report the synthesis and structure–activity relationship of a series of chiral alkoxymethyl morpholine analogs. Our efforts have culminated in the identification of (S)-2-(((6-chloropyridin-2-yl) oxy)methyl)-4-((6-fluoro-1H-indol-3-yl)methyl)morpholine as a novel potent and selective dopamine D4 receptor antagonist with selectivity against the other dopamine receptors tested (
- Published
- 2016
31. Re-exploration of the mGlu1 PAM Ro 07-11401 scaffold: Discovery of analogs with improved CNS penetration despite steep SAR
- Author
-
Colleen M. Niswender, P. Jeffrey Conn, Tahj M. Starr, Anna L. Blobaum, Hyekyung P. Cho, Pedro M. Garcia-Barrantes, and Craig W. Lindsley
- Subjects
0301 basic medicine ,Scaffold ,Allosteric modulator ,Drug discovery ,Chemistry ,Organic Chemistry ,Clinical Biochemistry ,Pharmaceutical Science ,Pharmacology ,Biochemistry ,PAM activity ,Cns penetration ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Metabotropic glutamate receptor ,Drug Discovery ,Biophysics ,Molecular Medicine ,Structure–activity relationship ,Molecular Biology ,030217 neurology & neurosurgery - Abstract
This letter describes the re-exploration of the mGlu1 PAM Ro 07-11401 scaffold through a multi-dimensional, iterative parallel synthesis approach. Unlike recent series of mGlu1 PAMs with robust SAR, the SAR around the Ro 07-11401 structure was incredibly steep (only ∼6 of 200 analogs displayed mGlu1 PAM activity), and reminiscent of the CPPHA mGlu5 PAM scaffold. Despite the steep SAR, two new thiazole derivatives were discovered with improved in vitro DMPK profiles and ∼3- to 4-fold improvement in CNS exposure (Kps 1.01-1.19); albeit, with a ∼3-fold diminution in mGlu1 PAM potency, yet comparable efficacy (∼5-fold leftward shift of the glutamate concentration-response curve at 10μM). Thus, this effort has provided additional CNS penetrant mGlu1 PAM tools in a different chemotype than the VU0486321 scaffold. These compounds will permit a better understanding of the pharmacology and therapeutic potential of selective mGlu1 activation, while highlighting the steep SAR challenges that can often be encountered in GPCR allosteric modulator discovery.
- Published
- 2016
32. N-Alkylpyrido[1′,2′:1,5]pyrazolo-[4,3-d]pyrimidin-4-amines: A new series of negative allosteric modulators of mGlu1/5 with CNS exposure in rodents
- Author
-
Frank W. Byers, Colleen M. Niswender, Ryan D. Morrison, Daryl F. Venable, P. Jeffrey Conn, Anna L. Blobaum, Craig W. Lindsley, Andrew S. Felts, Carrie K. Jones, J. Scott Daniels, Kyle A. Emmitte, and Alice L. Rodriguez
- Subjects
Central Nervous System ,Male ,0301 basic medicine ,Clinical Biochemistry ,Allosteric regulation ,Pharmaceutical Science ,Pharmacology ,Receptors, Metabotropic Glutamate ,Biochemistry ,Article ,Rats, Sprague-Dawley ,Mice ,Structure-Activity Relationship ,03 medical and health sciences ,0302 clinical medicine ,Allosteric Regulation ,Drug Discovery ,Animals ,Molecular Biology ,Dose-Response Relationship, Drug ,Molecular Structure ,Chemistry ,Metabotropic glutamate receptor 5 ,Metabotropic glutamate receptor 4 ,Organic Chemistry ,Metabotropic glutamate receptor 7 ,Rats ,Pyrimidines ,030104 developmental biology ,Metabotropic glutamate receptor ,Pyrazoles ,Molecular Medicine ,Metabotropic glutamate receptor 1 ,Metabotropic glutamate receptor 3 ,Metabotropic glutamate receptor 2 ,030217 neurology & neurosurgery - Abstract
Selective negative allosteric modulators (NAMs) of each of the group I metabotropic glutamate receptors (mGlu1 and mGlu5) have been well characterized in the literature and offer potential as therapeutics in several disorders of the central nervous system (CNS). Still, compounds that are potent mGlu1/5 NAMs with selectivity versus the other six members of the mGlu family as well as the balance of properties required for use in vivo are lacking. A medicinal chemistry effort centered on the identification of a lead series with the potential of delivering such compounds is described in this Letter. Specifically, a new class of pyrido[1′,2′:1,5]pyrazolo[4,3-d]pyrimidin-4-amines was designed as a novel isosteric replacement for 4-aminoquinazolines, and compounds from within this chemotype exhibited dual NAM activity at both group I mGlus. One compound, VU0467558 (29), demonstrated near equipotent activity at both receptors, selectivity versus other mGlus, a favorable ancillary pharmacology profile, and CNS exposure in rodents.
- Published
- 2016
33. Lead optimization of the VU0486321 series of mGlu 1 PAMs. Part 2: SAR of alternative 3-methyl heterocycles and progress towards an in vivo tool
- Author
-
Colleen M. Niswender, Anna L. Blobaum, P. Jeffrey Conn, Craig W. Lindsley, Adam M. Metts, Hyekyung P. Cho, and Pedro M. Garcia-Barrantes
- Subjects
0301 basic medicine ,Stereochemistry ,Clinical Biochemistry ,Allosteric regulation ,Pharmaceutical Science ,Receptors, Metabotropic Glutamate ,01 natural sciences ,Biochemistry ,Article ,Cns penetration ,Structure-Activity Relationship ,03 medical and health sciences ,Allosteric Regulation ,Coumarins ,Heterocyclic Compounds ,In vivo ,Drug Discovery ,Animals ,Humans ,Structure–activity relationship ,Furans ,Molecular Biology ,010405 organic chemistry ,Chemistry ,Organic Chemistry ,Genetic data ,Rats ,0104 chemical sciences ,030104 developmental biology ,Schizophrenia ,Biophysics ,Molecular Medicine ,Antipsychotic Agents ,Half-Life ,Protein Binding - Abstract
This letter describes the further lead optimization of the VU0486321 series of mGlu1 positive allosteric modulators (PAMs), driven by recent genetic data linking loss of function GRM1 to schizophrenia. Steep and caveat-laden SAR plagues the series, but ultimately potent mGlu1 PAMs (EC50s ~ 5 nM) have resulted with good DMPK properties (low intrinsic clearance, clean CYP profile, modest Fu) and CNS penetration (Kps 0.25 to 0.97), along with up to >450-fold selectivity versus mGlu4 and mGlu5.
- Published
- 2016
34. Conservative Secondary Shell Substitution In Cyclooxygenase-2 Reduces Inhibition by Indomethacin Amides and Esters via Altered Enzyme Dynamics
- Author
-
Terry P. Lybrand, Jeffery J. Prusakiewicz, Christopher W. Moth, Anna L. Blobaum, Dapo Akingbade, Shu Xu, Carol A. Rouzer, Aaron T. Jacobs, Kebreab Ghebreselasie, Lawrence J. Marnett, and Mary E. Konkle
- Subjects
0301 basic medicine ,Stereochemistry ,Carboxylic acid ,Indomethacin ,Biochemistry ,Article ,Protein Structure, Secondary ,Structure-Activity Relationship ,03 medical and health sciences ,Enzyme activator ,chemistry.chemical_compound ,Amide ,Structure–activity relationship ,Moiety ,chemistry.chemical_classification ,030102 biochemistry & molecular biology ,biology ,Chemistry ,Computational Biology ,Active site ,Esters ,Amides ,3. Good health ,Enzyme Activation ,Enzyme ,Cyclooxygenase 2 ,biology.protein ,Cyclooxygenase - Abstract
The cyclooxygenase enzymes (COX-1 and COX-2) are the therapeutic targets of nonsteroidal anti-inflammatory drugs (NSAIDs). Neutralization of the carboxylic acid moiety of the NSAID indomethacin to an ester or amide functionality confers COX-2 selectivity, but the molecular basis for this selectivity has not been completely revealed through mutagenesis studies and/or X-ray crystallographic attempts. We expressed and assayed a number of divergent secondary shell COX-2 active site mutants and found that a COX-2 to COX-1 change at position 472 (Leu in COX-2, Met in COX-1) reduced the potency of enzyme inhibition by a series of COX-2-selective indomethacin amides and esters. In contrast, the potencies of indomethacin, arylacetic acid, propionic acid, and COX-2-selective diarylheterocycle inhibitors were either unaffected or only mildly affected by this mutation. Molecular dynamics simulations revealed identical equilibrium enzyme structures around residue 472; however, calculations indicated that the L472M mutation impacted local low-frequency dynamical COX constriction site motions by stabilizing the active site entrance and slowing constriction site dynamics. Kinetic analysis of inhibitor binding is consistent with the computational findings.
- Published
- 2015
35. Lead optimization of the VU0486321 series of mGlu1 PAMs. Part 1: SAR of modifications to the central aryl core
- Author
-
Colleen M. Niswender, P. Jeffrey Conn, Pedro M. Garcia-Barrantes, Anna L. Blobaum, Hyekyung P. Cho, and Craig W. Lindsley
- Subjects
Stereochemistry ,Clinical Biochemistry ,Allosteric regulation ,Pharmaceutical Science ,Phthalimides ,Computational biology ,Plasma protein binding ,Receptors, Metabotropic Glutamate ,Biochemistry ,Article ,Structure-Activity Relationship ,chemistry.chemical_compound ,Allosteric Regulation ,Coumarins ,Drug Discovery ,Animals ,Humans ,Structure–activity relationship ,Furans ,Molecular Biology ,Aryl ,Organic Chemistry ,Brain ,Genetic data ,Stereoisomerism ,First generation ,Rats ,chemistry ,Microsomes, Liver ,Molecular Medicine - Abstract
This Letter describes the lead optimization of the VU0486321 series of mGlu1 positive allosteric modulators (PAMs). While first generation PAMs from Roche were reported in the late 1990s, little effort has focused on the development of mGlu1 PAMs since. New genetic data linking loss-of-function mutant mGlu1 receptors to schizophrenia, bipolar disorder and other neuropsychiatric disorders has rekindled interest in the target, but the ideal in vivo probe, for example, with good PK, brain penetration and low plasma protein binding, for robust target validation has been lacking. Here we describe the first modifications to the central aryl core of the VU0486321 series, where robust SAR was noted. Moreover, structural variants were identified that imparted selectivity (up to >793-fold) versus mGlu4.
- Published
- 2015
36. Development of Novel, CNS Penetrant Positive Allosteric Modulators for the Metabotropic Glutamate Receptor Subtype 1 (mGlu1), Based on an N-(3-Chloro-4-(1,3-dioxoisoindolin-2-yl)phenyl)-3-methylfuran-2-carboxamide Scaffold, That Potentiate Wild Type and Mutant mGlu1 Receptors Found in Schizophrenics
- Author
-
Colleen M. Niswender, Hyekyung P. Cho, Jerri M. Rook, Anna L. Blobaum, P. Jeffrey Conn, Pedro M. Garcia-Barrantes, Zixiu Xiang, Craig W. Lindsley, Charles W. Locuson, and Frank W. Byers
- Subjects
Central Nervous System ,Receptor, Metabotropic Glutamate 5 ,Molecular Conformation ,Pharmacology ,Receptors, Metabotropic Glutamate ,Article ,Structure-Activity Relationship ,stomatognathic system ,parasitic diseases ,Drug Discovery ,Animals ,Humans ,GABA Modulators ,GABA Agonists ,Epilepsy ,Chemistry ,Metabotropic glutamate receptor 5 ,Metabotropic glutamate receptor 4 ,Metabotropic glutamate receptor 7 ,Rats ,Biochemistry ,Metabotropic glutamate receptor ,Schizophrenia ,Molecular Medicine ,Metabotropic glutamate receptor 1 ,Metabotropic glutamate receptor 3 ,Metabotropic glutamate receptor 2 ,Half-Life - Abstract
The therapeutic potential of selective mGlu1 activation is vastly unexplored relative to the other group I mGlu receptor, mGlu5; therefore, our lab has focused considerable effort toward developing mGlu1 positive allosteric modulators (PAMs) suitable as in vivo proof of concept tool compounds. Optimization of a series of mGlu1 PAMs based on an N-(3-chloro-4-(1,3-dioxoisoindolin-2-yl)phenyl)-3-methylfuran-2-carboxamide scaffold provided 17e, a potent (mGlu1 EC50 = 31.8 nM) and highly CNS penetrant (brain to plasma ratio (Kp) of 1.02) mGlu1 PAM tool compound, that potentiated not only wild-type human mGlu1 but also mutant mGlu1 receptors derived from deleterious GRM1 mutations found in schizophrenic patients. Moreover, both electrophysiological and in vivo studies indicate the mGlu1 ago-PAMs/PAMs do not possess the same epileptiform adverse effect liability as mGlu5 ago-PAMs/PAMs and maintain temporal activity suggesting a broader therapeutic window.
- Published
- 2015
37. Discovery of Tricyclic Triazolo- and Imidazopyridine Lactams as M(1) Positive Allosteric Modulators
- Author
-
Jerri M. Rook, Colleen M. Niswender, Kyle A. Emmitte, Craig W. Lindsley, Jonathan W. Dickerson, P. Jeffrey Conn, Vincent B. Luscombe, Changho Han, Hyekyung P. Cho, Anna L. Blobaum, Julie L. Engers, Kaelyn S. Lingenfelter, Aaron M. Bender, Jacob J. Kalbfleisch, and Bruce J. Melancon
- Subjects
Imidazopyridine ,Lactams ,Physiology ,Stereochemistry ,Pyridines ,Cognitive Neuroscience ,Allosteric regulation ,Muscarinic Agonists ,Biochemistry ,Article ,03 medical and health sciences ,chemistry.chemical_compound ,Mice ,0302 clinical medicine ,Allosteric Regulation ,In vivo ,Muscarinic acetylcholine receptor ,Drug Discovery ,Animals ,Humans ,030304 developmental biology ,chemistry.chemical_classification ,0303 health sciences ,Receptor, Muscarinic M1 ,Imidazoles ,Cell Biology ,General Medicine ,Rats ,chemistry ,Lactam ,Cholinergic ,Triazolopyridine ,030217 neurology & neurosurgery ,Tricyclic - Abstract
This Letter describes the chemical optimization of a new series of muscarinic acetylcholine receptor subtype 1 (M(1)) positive allosteric modulators (PAMs) based on novel tricyclic triazolo- and imidazopyridine lactam cores, devoid of M(1) agonism, e.g., no M(1) ago-PAM activity, in high expressing recombinant cell lines. While all the new tricyclic congeners afforded excellent rat pharmacokinetic (PK) properties (CL(p) < 8 mL/min/kg and t(1/2) > 5 h), regioisomeric triazolopyridine analogues were uniformly not CNS penetrant (K(p) < 0.05), despite a lack of hydrogen bond donors. However, removal of a single nitrogen atom to afford imidazopyridine derivatives proved to retain the excellent rat PK and provide high CNS penetration (K(p) > 2), despite inclusion of a basic nitrogen. Moreover, 24c was devoid of M(1) agonism in high expressing recombinant cell lines and did not induce cholinergic seizures in vivo in mice. Interestingly, all of the new M(1) PAMs across the diverse tricyclic heterocyclic cores possessed equivalent CNS MPO scores (>4.5), highlighting the value of both “medicinal chemist’s eye” and experimental data, e.g., not sole reliance (or decision bias) on in silico calculated properties, for parameters as complex as CNS penetration.
- Published
- 2018
38. Discovery, characterization, and preclinical development of a Kir4.1 ( KCNJ10 ) inhibitor for the treatment of hypertension
- Author
-
Eric E. Figueroa, Jerod S. Denton, Sujay V. Kharade, Anna L. Blobaum, Corey R. Hopkins, Meghan Kramer, Haruto Kurata, and Craig W. Lindsley
- Subjects
business.industry ,Genetics ,Medicine ,Pharmacology ,business ,Molecular Biology ,Biochemistry ,Biotechnology - Published
- 2018
39. Action at a Distance
- Author
-
Shu Xu, Scott W. Rowlinson, Kebreab Ghebreselasie, Lawrence J. Marnett, Shalley N. Kudalkar, William R. Birmingham, Kelsey C. Duggan, Surajit Banerjee, and Anna L. Blobaum
- Subjects
chemistry.chemical_classification ,biology ,Flurbiprofen ,Mutagenesis ,Tryptophan ,Active site ,Cell Biology ,Biochemistry ,chemistry.chemical_compound ,Enzyme ,chemistry ,Enzyme inhibitor ,biology.protein ,medicine ,Cyclooxygenase ,Molecular Biology ,Prostaglandin G2 ,medicine.drug - Abstract
Cyclooxygenase enzymes (COX-1 and COX-2) catalyze the conversion of arachidonic acid to prostaglandin G2. The inhibitory activity of rapid, reversible COX inhibitors (ibuprofen, naproxen, mefenamic acid, and lumiracoxib) demonstrated a significant increase in potency and time dependence of inhibition against double tryptophan murine COX-2 mutants at the 89/90 and 89/119 positions. In contrast, the slow, time-dependent COX inhibitors (diclofenac, indomethacin, and flurbiprofen) were unaffected by those mutations. Further mutagenesis studies suggested that mutation at position 89 was principally responsible for the changes in inhibitory potency of rapid, reversible inhibitors, whereas mutation at position 90 may exert some effect on the potency of COX-2-selective diarylheterocycle inhibitors; no effect was observed with mutation at position 119. Several crystal structures with or without NSAIDs indicated that placement of a bulky residue at position 89 caused a closure of a gap at the lobby, and alteration of histidine to tryptophan at position 90 changed the electrostatic profile of the side pocket of COX-2. Thus, these two residues, especially Val-89 at the lobby region, are crucial for the entrance and exit of some NSAIDs from the COX active site.
- Published
- 2015
40. Design and Synthesis of N-Aryl Phenoxyethoxy Pyridinones as Highly Selective and CNS Penetrant mGlu3 NAMs
- Author
-
Ryan D. Morrison, Sean R. Bollinger, P. Jeffrey Conn, Alice L. Rodriguez, Colleen M. Niswender, Michael Bubser, Craig W. Lindsley, Anna L. Blobaum, Julie L. Engers, Sichen Chang, Kyle A. Emmitte, Madeline F. Long, Rebecca L. Weiner, Katrina A. Bollinger, Megan M. Breiner, Carrie K. Jones, and Thomas M. Bridges
- Subjects
0301 basic medicine ,Stereochemistry ,Aryl ,Organic Chemistry ,Penetration (firestop) ,Highly selective ,Rat brain ,Biochemistry ,Tail suspension test ,03 medical and health sciences ,chemistry.chemical_compound ,030104 developmental biology ,0302 clinical medicine ,chemistry ,In vivo ,Drug Discovery ,IC50 ,030217 neurology & neurosurgery - Abstract
Herein, we detail the optimization of the mGlu3 NAM, VU0650786, via a reductionist approach to afford a novel, simplified mGlu3 NAM scaffold that engenders potent and selective mGlu3 inhibition (mGlu3 IC50 = 245 nM, mGlu2 IC50 > 30 μM) with excellent central nervous system penetration (rat brain/plasma Kp = 1.2, Kp,uu = 0.40). Moreover, this new chemotype, exemplified by VU6010572, requires only four synthetic steps and displays improved physiochemical properties and in vivo efficacy in a mouse tail suspension test (MED = 3 mg/kg i.p.).
- Published
- 2017
41. Contributions of Protease-Activated Receptors PAR1 and PAR4 to Thrombin-Induced GPIIbIIIa Activation in Human Platelets
- Author
-
Craig W. Lindsley, Anna L. Blobaum, Kayla J. Temple, Shaun R. Stauffer, Jae G. Maeng, Heidi E. Hamm, and Matthew T. Duvernay
- Subjects
0301 basic medicine ,Blood Platelets ,Context (language use) ,030204 cardiovascular system & hematology ,Ligands ,Fibrin ,03 medical and health sciences ,0302 clinical medicine ,Thrombin ,medicine ,Humans ,Platelet ,Receptor, PAR-1 ,Platelet activation ,Receptor ,Pharmacology ,biology ,Chemistry ,Antagonist ,Integrin beta3 ,Articles ,030104 developmental biology ,Biochemistry ,Platelet Glycoprotein GPIb-IX Complex ,Biophysics ,biology.protein ,Molecular Medicine ,Receptors, Thrombin ,Pharmacophore ,medicine.drug ,Signal Transduction - Abstract
Human platelets display a unique dual receptor system for responding to its primary endogenous activator, α-thrombin. Because of the lack of efficacious antagonists, the field has relied on synthetic peptides and pepducins to describe protease-activated receptor PAR1 and PAR4 signaling. The precise contributions of each receptor have not been established in the context of thrombin. We took advantage of newly discovered PAR antagonists to contrast the contribution of PAR1 and PAR4 to thrombin-mediated activation of the platelet fibrin receptor (GPIIbIIIa). PAR1 is required for platelet activation at low but not high concentrations of thrombin, and maximal platelet activation at high concentrations of thrombin requires PAR4. As the concentration of thrombin is increased, PAR1 signaling is quickly overcome by PAR4 signaling, leaving a narrow window of low thrombin concentrations that exclusively engage PAR1. PAR4 antagonism reduces the maximum thrombin response by over 50%. Thus, although the PAR1 response still active at higher concentrations of thrombin, this response is superseded by PAR4. Truncation of a known PAR4 antagonist and identification of the minimum pharmacophore converted the mechanism of inhibition from noncompetitive to competitive, such that the antagonist could be outcompeted by increasing doses of the ligand. Fragments retained efficacy against both soluble and tethered ligands with lower cLogP values and an increased free fraction in plasma. These reversible, competitive compounds represent a route toward potentially safer PAR4 antagonists for clinical utility and the development of tools such as radioligands and positron emission tomography tracers that are not currently available to the field for this target.
- Published
- 2017
42. Prefrontal Cortex-Mediated Impairments in a Genetic Model of NMDA Receptor Hypofunction Are Reversed by the Novel M1 PAM VU6004256
- Author
-
Sean P. Moran, Carrie K. Jones, Hyekyung P. Cho, Catharine A. Mielnik, Craig W. Lindsley, Jacob Ball, Amy J. Ramsey, Anna L. Blobaum, Michael Bubser, P. Jeffrey Conn, Masahito Abe, Zhuoyan Lu, Kellie D. Nance, Colleen M. Niswender, Robert W. Gould, and Michael Grannan
- Subjects
0301 basic medicine ,Male ,Mice, 129 Strain ,Physiology ,Cognitive Neuroscience ,Allosteric regulation ,Cholinergic Agents ,Drug Evaluation, Preclinical ,Action Potentials ,Prefrontal Cortex ,Mice, Transgenic ,Nerve Tissue Proteins ,Motor Activity ,Biochemistry ,Muscarinic agonist ,Heterocyclic Compounds, 4 or More Rings ,Receptors, N-Methyl-D-Aspartate ,Article ,Tissue Culture Techniques ,03 medical and health sciences ,0302 clinical medicine ,mental disorders ,Genetic model ,Muscarinic acetylcholine receptor ,Conditioning, Psychological ,Animals ,Prefrontal cortex ,Nootropic Agents ,musculoskeletal, neural, and ocular physiology ,Long-Term Synaptic Depression ,Pyramidal Cells ,Glutamate receptor ,Recognition, Psychology ,Cell Biology ,General Medicine ,Muscarinic acetylcholine receptor M1 ,Fear ,Mice, Inbred C57BL ,Disease Models, Animal ,030104 developmental biology ,nervous system ,Gene Knockdown Techniques ,NMDA receptor ,Psychology ,Cognition Disorders ,Neuroscience ,030217 neurology & neurosurgery - Abstract
Abnormalities in the signaling of the N-methyl-D-aspartate subtype of the glutamate receptor (NMDAR) within cortical and limbic brain regions are thought to underlie many of the complex cognitive and affective symptoms observed in individuals with schizophrenia. The M1 muscarinic acetylcholine receptor (mAChR) subtype is a closely coupled signaling partner of the NMDAR. Accumulating evidence suggests that development of selective positive allosteric modulators (PAMs) of the M1 receptor represent an important treatment strategy for the potential normalization of disruptions in NMDAR signaling in patients with schizophrenia. In the present studies, we evaluated the effects of the novel and highly potent M1 PAM, VU6004256, in ameliorating selective prefrontal cortical (PFC)-mediated physiologic and cognitive abnormalities in a genetic mouse model of global reduction in the NR1 subunit of the NMDAR (NR1 knockdown [KD]). Using slice-based extracellular field potential recordings, deficits in muscarinic agonist-induced long-term depression (LTD) in layer V of the PFC in the NR1 KD mice were normalized with bath application of VU6004256. Systemic administration of VU6004256 also reduced excessive pyramidal neuron firing in layer V PFC neurons in awake, freely moving NR1 KD mice. Moreover, selective potentiation of M1 by VU6004256 reversed the performance impairments of NR1 KD mice observed in two preclinical models of PFC-mediated learning, specifically the novel object recognition and cue-mediated fear conditioning tasks. VU6004256 also produced a robust, dose-dependent reduction in the hyperlocomotor activity of NR1 KD mice. Taken together, the current findings provide further support for M1 PAMs as a novel therapeutic approach for the PFC-mediated impairments in schizophrenia.
- Published
- 2016
43. Discovery of VU0409106: A negative allosteric modulator of mGlu5 with activity in a mouse model of anxiety
- Author
-
P. Jeffrey Conn, Daryl F. Venable, Anna L. Blobaum, Jason Manka, Frank W. Byers, J. Scott Daniels, Colleen M. Niswender, Brittney S. Bates, Andrew S. Felts, Kyle A. Emmitte, Craig W. Lindsley, Alice L. Rodriguez, Carrie K. Jones, and Ryan D. Morrison
- Subjects
Allosteric modulator ,Receptor, Metabotropic Glutamate 5 ,Clinical Biochemistry ,Allosteric regulation ,Pharmaceutical Science ,Anxiety ,Pharmacology ,Biochemistry ,Article ,Rats sprague dawley ,Marble burying ,Mice ,Structure-Activity Relationship ,Allosteric Regulation ,Drug Discovery ,medicine ,Animals ,Structure–activity relationship ,Molecular Biology ,Chemistry ,Drug discovery ,Organic Chemistry ,Glutamate receptor ,Thiazoles ,Benzamides ,Molecular Medicine ,medicine.symptom ,Allosteric Site - Abstract
Development of SAR in an aryl ether series of mGlu5 NAMs leading to the identification of tool compound VU0409106 is described in this Letter. VU0409106 is a potent and selective negative allosteric modulator of mGlu5 that binds at the known allosteric binding site and demonstrates good CNS exposure following intraperitoneal dosing in mice. VU0409106 also proved efficacious in a mouse marble burying model of anxiety, an assay known to be sensitive to mGlu5 antagonists as well as clinically efficacious anxiolytics.
- Published
- 2013
44. Octahydropyrrolo[3,4-c]pyrrole negative allosteric modulators of mGlu1
- Author
-
Colleen M. Niswender, Anna L. Blobaum, Craig W. Lindsley, Jason Manka, Alice L. Rodriguez, P. Jeffrey Conn, Kyle A. Emmitte, J. Scott Daniels, Hyekyung P. Cho, Daryl F. Venable, and Ryan D. Morrison
- Subjects
Allosteric modulator ,Stereochemistry ,Clinical Biochemistry ,Allosteric regulation ,Pharmaceutical Science ,Plasma protein binding ,Receptors, Metabotropic Glutamate ,Ring (chemistry) ,Biochemistry ,Article ,Structure-Activity Relationship ,chemistry.chemical_compound ,Allosteric Regulation ,Cytochrome P-450 Enzyme System ,Drug Discovery ,Animals ,Cytochrome P-450 Enzyme Inhibitors ,Humans ,Molecule ,Structure–activity relationship ,Pyrroles ,Enzyme Inhibitors ,Molecular Biology ,Pyrrole ,Dose-Response Relationship, Drug ,Molecular Structure ,Organic Chemistry ,Rats ,Piperazine ,chemistry ,Molecular Medicine - Abstract
Development of SAR in an octahydropyrrolo[3,4-c]pyrrole series of negative allosteric modulators of mGlu1 using a functional cell-based assay is described in this Letter. The octahydropyrrolo[3,4-c]pyrrole scaffold was chosen as an isosteric replacement for the piperazine ring found in the initial hit compound. Characterization of selected compounds in protein binding assays was used to identify the most promising analogs, which were then profiled in P450 inhibition assays in order to further assess the potential for drug-likeness within this series of compounds.
- Published
- 2013
45. The 2′-Trifluoromethyl Analogue of Indomethacin Is a Potent and Selective COX-2 Inhibitor
- Author
-
Lawrence J. Marnett, Md. Jashim Uddin, Carol A. Rouzer, Brenda C. Crews, Andrew S. Felts, and Anna L. Blobaum
- Subjects
Letter ,Prostaglandin ,Pharmacology ,nonsteroidal anti-inflammatory drug ,01 natural sciences ,Biochemistry ,03 medical and health sciences ,chemistry.chemical_compound ,In vivo ,Drug Discovery ,arachidonic acid ,Medicine ,Potency ,IC50 ,030304 developmental biology ,0303 health sciences ,Trifluoromethyl ,biology ,010405 organic chemistry ,business.industry ,Organic Chemistry ,coxib ,Cyclooxygenase ,3. Good health ,0104 chemical sciences ,chemistry ,inflammation ,biology.protein ,COX-2 inhibitor ,Arachidonic acid ,prostaglandin ,business - Abstract
Indomethacin is a potent, time-dependent, nonselective inhibitor of the cyclooxygenase enzymes (COX-1 and COX-2). Deletion of the 2′-methyl group of indomethacin produces a weak, reversible COX inhibitor, leading us to explore functionality at that position. Here, we report that substitution of the 2′-methyl group of indomethacin with trifluoromethyl produces CF3–indomethacin, a tight-binding inhibitor with kinetic properties similar to those of indomethacin and unexpected COX-2 selectivity (IC50 mCOX-2 = 267 nM; IC50 oCOX-1 > 100 μM). Studies with site-directed mutants reveal that COX-2 selectivity results from insertion of the CF3 group into a small hydrophobic pocket formed by Ala-527, Val-349, Ser-530, and Leu-531 and projection of the methoxy group toward a side pocket bordered by Val-523. CF3–indomethacin inhibited COX-2 activity in human head and neck squamous cell carcinoma cells and exhibited in vivo anti-inflammatory activity in the carrageenan-induced rat paw edema model with similar potency to that of indomethacin.
- Published
- 2013
46. Discovery of a selective M4 positive allosteric modulator based on the 3-amino-thieno[2,3-b]pyridine-2-carboxamide scaffold: Development of ML253, a potent and brain penetrant compound that is active in a preclinical model of schizophrenia
- Author
-
Carrie K. Jones, Colleen M. Niswender, Bruce J. Melancon, Thomas M. Bridges, Uyen M. Le, Daryl F. Venable, Douglas J. Sheffler, J. Scott Daniels, Craig W. Lindsley, Atin Lamsal, Paige N. Vinson, Corey R. Hopkins, Alice L. Rodriguez, Thomas J. Utley, P. Jeffrey Conn, Michael R. Wood, and Anna L. Blobaum
- Subjects
Allosteric modulator ,medicine.drug_class ,Stereochemistry ,Chemistry ,Organic Chemistry ,Clinical Biochemistry ,Allosteric regulation ,Pharmaceutical Science ,Carboxamide ,Plasma protein binding ,Pharmacology ,Biochemistry ,Drug Discovery ,Muscarinic acetylcholine receptor ,medicine ,Molecular Medicine ,Structure–activity relationship ,Cholinergic ,Receptor ,Molecular Biology - Abstract
Herein we report a next generation muscarinic receptor 4 (M(4)) positive allosteric modulator (PAM), ML253 which exhibits nanomolar activity at both the human (EC(50)=56 nM) and rat (EC(50)=176 nM) receptors and excellent efficacy by the left-ward shift of the ACh concentration response curve (fold shift, human=106; rat=50). In addition, ML253 is selective against the four other muscarinic subtypes, displays excellent CNS exposure and is active in an amphetamine-induced hyperlocomotion assay.
- Published
- 2013
47. Development and Antiparkinsonian Activity of VU0418506, a Selective Positive Allosteric Modulator of Metabotropic Glutamate Receptor 4 Homomers without Activity at mGlu2/4 Heteromers
- Author
-
P. Jeffrey Conn, Colleen M. Niswender, Michael Bubser, J. Scott Daniels, Darren W. Engers, Analisa D. Thompson Gray, Matthew T. Loch, Xin Lin, Craig W. Lindsley, Anna L. Blobaum, Alice L. Rodriguez, Carrie K. Jones, Corey R. Hopkins, and Jonathan A. Javitch
- Subjects
0301 basic medicine ,Allosteric modulator ,Apomorphine ,Physiology ,Cognitive Neuroscience ,Glutamic Acid ,Pharmacology ,Biology ,Receptors, Metabotropic Glutamate ,Transfection ,Biochemistry ,Article ,Antiparkinson Agents ,Rats, Sprague-Dawley ,03 medical and health sciences ,0302 clinical medicine ,Allosteric Regulation ,Forelimb ,Animals ,Humans ,Oxidopamine ,Catalepsy ,Metabotropic glutamate receptor 5 ,Metabotropic glutamate receptor 4 ,Metabotropic glutamate receptor 7 ,Brain ,Parkinson Disease ,Cell Biology ,General Medicine ,Rats ,Disease Models, Animal ,030104 developmental biology ,HEK293 Cells ,Metabotropic glutamate receptor ,Dopamine Agonists ,Metabotropic glutamate receptor 1 ,Haloperidol ,Metabotropic glutamate receptor 3 ,Metabotropic glutamate receptor 2 ,Neuroscience ,030217 neurology & neurosurgery ,Antipsychotic Agents - Abstract
Metabotropic glutamate receptor 4 (mGlu4) is emerging as a potential therapeutic target for numerous central nervous system indications, including Parkinson’s disease (PD). As the glutamate binding sites among the eight mGlu receptors are highly conserved, modulation of receptor activity via allosteric sites within the receptor transmembrane domains using positive and negative allosteric modulators (PAMs and NAMs, respectively) has become a common strategy. We and others have used PAMs targeting mGlu4 to show that potentiation of receptor signaling induces antiparkinsonian activity in a variety of PD animal models, including haloperidol-induced catalepsy and 6-hydroxydopamine-induced lesion. Recently, mGlu4 has been reported to form heteromeric complexes with other mGlu receptor subtypes, such as mGlu2, and the resulting heteromer exhibits a distinct pharmacological profile in response to allosteric modulators. For example, some mGlu4 PAMs do not appear to potentiate glutamate activity when mGlu2 and mGlu4 are coexpressed, whereas other compounds potentiate mGlu4 responses regardless of mGlu2 coexpression. We report here the discovery and characterization of VU0418506, a novel mGlu4 PAM with activity in rodent PD models. Using pharmacological approaches and Complemented Donor–Acceptor resonance energy transfer (CODA-RET) technology, we find that VU0418506 does not potentiate agonist-induced activity when mGlu2 and mGlu4 are heterodimerized, suggesting that the antiparkinsonian action of mGlu4 PAMs can be induced by compounds without activity at mGlu2/4 heteromers.
- Published
- 2016
48. Optimization of the choline transporter (CHT) inhibitor ML352: Development of VU6001221, an improved in vivo tool compound
- Author
-
Anna L. Blobaum, Jane Wright, Jerri M. Rook, Christopher J. Tarr, Jeanette L. Bertron, Jonathan W. Dickerson, Elizabeth A. Ennis, Charles W. Locuson, Craig W. Lindsley, and Randy D. Blakely
- Subjects
0301 basic medicine ,Stereochemistry ,Clinical Biochemistry ,Pharmaceutical Science ,Pharmacology ,Biochemistry ,03 medical and health sciences ,chemistry.chemical_compound ,Inhibitory Concentration 50 ,Structure-Activity Relationship ,0302 clinical medicine ,Piperidines ,In vivo ,Drug Discovery ,Extracellular ,Structure–activity relationship ,Choline ,Animals ,Molecular Biology ,Oxazoles ,Acetylcholine receptor ,biology ,Dose-Response Relationship, Drug ,Chemistry ,Membrane transport protein ,Organic Chemistry ,Membrane Transport Proteins ,Isoxazoles ,Rats ,Choline transporter ,030104 developmental biology ,Nicotinic agonist ,Benzamides ,biology.protein ,Molecular Medicine ,030217 neurology & neurosurgery ,Half-Life - Abstract
This Letter describes the further lead optimization of the CHT inhibitor probe, ML352 (VU0476201), and the development of VU6001221, an improved in vivo tool. A multi-dimensional optimization effort encountered steep SAR, and ultimately, subtle tuning of the electronics of the central phenyl core provided VU6001221, a CHT inhibitor with comparable potency for choline uptake inhibition as ML352, yet improved PK and CNS penetration. Moreover, VU6001221 enabled evaluation, for the first time, of a CHT inhibitor in a standard preclinical rodent cognition model, novel object recognition (NOR). We observed VU6001221 to elicit a dose-responsive increase in NOR, raising the possibility of agonism of synaptic α7 nicotinic ACh receptors by elevated extracellular choline, that if confirmed would represent a novel molecular strategy to enhance cognition.
- Published
- 2016
49. ML418: The First Selective, Sub-Micromolar Pore Blocker of Kir7.1 Potassium Channels
- Author
-
Jerod S. Denton, Haruto Kurata, Rene Raphemot, Anna L. Blobaum, Daniel R. Swale, Craig W. Lindsley, Eric E. Figueroa, Sujay V. Kharade, Jens Meiler, Corey R. Hopkins, Karl R. Voigtritter, and Jonathan H. Sheehan
- Subjects
0301 basic medicine ,Models, Molecular ,Patch-Clamp Techniques ,Time Factors ,Physiology ,Cognitive Neuroscience ,Potassium ,chemistry.chemical_element ,Pharmacology ,Biology ,Transfection ,Biochemistry ,Article ,Membrane Potentials ,Contractility ,03 medical and health sciences ,Structure-Activity Relationship ,0302 clinical medicine ,Potassium Channel Blockers ,Animals ,Humans ,Potassium Channels, Inwardly Rectifying ,Alanine ,Dose-Response Relationship, Drug ,Inward-rectifier potassium ion channel ,Glutamate receptor ,Myometrium ,Cell Biology ,General Medicine ,Potassium channel ,030104 developmental biology ,HEK293 Cells ,chemistry ,Mutation ,Mutagenesis, Site-Directed ,Melanocortin ,030217 neurology & neurosurgery - Abstract
The inward rectifier potassium (Kir) channel Kir7.1 (KCNJ13) has recently emerged as a key regulator of melanocortin signaling in the brain, electrolyte homeostasis in the eye, and uterine muscle contractility during pregnancy. The pharmacological tools available for exploring the physiology and therapeutic potential of Kir7.1 have been limited to relatively weak and non-selective small-molecule inhibitors. Here, we report the discovery in a fluorescence-based high-throughput screen of a novel Kir7.1 channel inhibitor, VU714. Site-directed mutagenesis of pore-lining amino acid residues identified Glutamate 149 and Alanine 150 as essential determinants of VU714 activity. Lead optimization with medicinal chemistry generated ML418, which exhibits sub-micromolar activity (IC50 = 310 nM) and superior selectivity over other Kir channels (at least 17-fold selective over Kir1.1, Kir2.1, Kir2.2, Kir2.3, Kir3.1/3.2, and Kir4.1) except for Kir6.2/SUR1 (equally potent). Evaluation in the EuroFins Lead Profiling panel of 64 GPCRs, ion-channels and transporters for off-target activity of ML418 revealed a relatively clean ancillary pharmacology. While ML418 exhibited low CLHEP in human microsomes which could be modulated with lipophilicity adjustments, it showed high CLHEP in rat microsomes regardless of lipophilicity. A subsequent in vivo PK study of ML418 by intraperitoneal (IP) administration (30 mg/kg dosage) revealed a suitable PK profile (Cmax = 0.20 µM and Tmax = 3 hours) and favorable CNS distribution (mouse brain:plasma Kp of 10.9 to support in vivo studies for in vivo studies. ML418, which represents the current state-of-the-art in Kir7.1 inhibitors, should be useful for exploring the physiology of Kir7.1 in vitro and in vivo.
- Published
- 2016
50. Discovery and characterization of a novel series of N-phenylsulfonyl-1H-pyrrole picolinamides as positive allosteric modulators of the metabotropic glutamate receptor 4 (mGlu4)
- Author
-
Corey R. Hopkins, Alice L. Rodriguez, Craig W. Lindsley, Colleen M. Niswender, Matthew T. Loch, Anna L. Blobaum, Yiu Yin Cheung, James M. Salovich, J. Scott Daniels, Rocco D. Gogliotti, P. Jeffrey Conn, and Ryan Morrison
- Subjects
Stereochemistry ,Clinical Biochemistry ,Allosteric regulation ,Pharmaceutical Science ,Receptors, Metabotropic Glutamate ,01 natural sciences ,Biochemistry ,Article ,Sulfone ,03 medical and health sciences ,chemistry.chemical_compound ,Structure-Activity Relationship ,0302 clinical medicine ,Allosteric Regulation ,Drug Discovery ,Structure–activity relationship ,Animals ,Pyrroles ,Picolinic Acids ,Molecular Biology ,Pyrrole ,Sulfonyl ,chemistry.chemical_classification ,Sulfonamides ,Metabotropic glutamate receptor 4 ,Organic Chemistry ,Triazoles ,0104 chemical sciences ,Rats ,010404 medicinal & biomolecular chemistry ,chemistry ,Microsomes, Liver ,Molecular Medicine ,030217 neurology & neurosurgery - Abstract
Herein we report the synthesis and characterization of a novel series of N-phenylsulfonyl-1H-pyrrole picolinamides as novel positive allosteric modulators of mGlu4. We detail our work towards finding phenyl replacements for the core scaffold of previously reported phenyl sulfonamides and phenyl sulfone compounds. Our efforts culminated in the identification of N-(1-((3,4-dimethylphenyl)sulfonyl)-1H-pyrrol-3-yl)picolinamide as a potent PAM of mGlu4.
- Published
- 2016
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.