11 results on '"Lisa Dvorak"'
Search Results
2. Discovery and SAR studies of 2-alkyl-3-phenyl-2,4,5,6,7,8-hexahydropyrazolo[3,4-d]azepines as 5-HT7/2 inhibitors leading to the identification of a clinical candidate
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Pascal Bonaventure, Brian Lord, Ian Fraser, Curt A. Dvorak, Nicholas I. Carruthers, Dale A. Rudolph, Timothy W. Lovenberg, Diane Nepomuceno, and Lisa Dvorak
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010405 organic chemistry ,5-HT2A receptor ,medicine.drug_class ,Chemistry ,Organic Chemistry ,Clinical Biochemistry ,Pharmaceutical Science ,Pharmacology ,Ligand (biochemistry) ,Receptor antagonist ,01 natural sciences ,Biochemistry ,0104 chemical sciences ,5-HT7 receptor ,010404 medicinal & biomolecular chemistry ,In vivo ,Drug Discovery ,medicine ,Molecular Medicine ,Inverse agonist ,Receptor ,Molecular Biology ,Ex vivo - Abstract
We report here the synthesis and characterization of a dual 5-HT7 / 5-HT2 receptor antagonist 3-(4-Fluoro-phenyl)-2-isopropyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene (4j). 4j is a high affinity 5-HT7 and 5-HT2A receptor ligand having a pKi = 8.1 at both receptors. It behaves as an antagonist in an in vitro functional assay for 5-HT2A and as an inverse agonist in an in vitro functional assay for 5-HT7. In a validated in vivo model for central 5-HT7 activity in rats, blockade of 5-carboxamidotryptamine (5-CT) induced hypothermia, 4j shows efficacy at low doses (ED50 = 0.05 mg/kg, p.o., 1 h) and maximal efficacy was observed at 0.3 mg/kg p.o. with a corresponding plasma concentration of ~27 ng/ml. In a validated in vivo model for central 5-HT2A activity, blockade of 2,5-dimethoxy-4-iodoamphetamine (DOI) induced head-twitches in mice, 4j shows efficacy at low doses with an ED50 = 0.3 mg/kg p.o. Ex vivo receptor binding studies demonstrate that 4j occupied 5-HT2A receptor binding sites in the frontal cortex of the rat brain with an ED50 in good agreement with the ED50 value for central functional effect mediated by 5-HT2A receptor (ED50 = 0.8 mg/kg, p.o., 1 h).
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- 2021
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3. The discovery and synthesis of JNJ 31020028, a small molecule antagonist of the Neuropeptide Y Y2 receptor
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Pascal Bonaventure, Jill A. Jablonowski, Timothy W. Lovenberg, John R. Atack, Swanson Devin M, Curt A. Dvorak, Mark Seierstad, Lisa Dvorak, Diane Nepomuceno, Dale A. Rudolph, Victoria D. Wong, Nicholas I. Carruthers, Chandra R. Shah, and Kirsten L. Morton
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Neuropeptide Y receptor Y1 ,Neuropeptide Y receptor Y2 ,Chemistry ,medicine.drug_class ,Stereochemistry ,Organic Chemistry ,Clinical Biochemistry ,Antagonist ,Pharmaceutical Science ,Receptor antagonist ,Neuropeptide Y receptor ,Biochemistry ,Combinatorial chemistry ,Small molecule ,Drug Discovery ,medicine ,Molecular Medicine ,Racemic mixture ,Enantiomer ,Molecular Biology - Abstract
A series of small molecules based on a chemotype identified from our compound collection were synthesized and tested for binding affinity (IC50) at the human Neuropeptide Y Y2 receptor (NPY Y2). Six of the 23 analogs tested possessed an NPY Y2 IC50 ⩽ 15 nM. One member of this series, JNJ 31020028, is a selective, high affinity, receptor antagonist existing as a racemic mixture. As such a synthetic route to the desired enantiomer was designed starting from commercially available (S)-(+)-mandelic acid.
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- 2011
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4. Heterocyclic replacement of the central phenyl core of diamine-based histamine H3 receptor antagonists
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Timothy W. Lovenberg, Lisa Dvorak, Jamin D. Boggs, Brian Lord, Curt Mazur, Swanson Devin M, Pascal Bonaventure, Richard Apodaca, Chandra R. Shah, Kirsten L. Morton, Ann J. Barbier, Mark A. Feinstein, Sandy J. Wilson, Nicholas I. Carruthers, and Wei Xiao
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Pharmacology ,Pyrazine ,Stereochemistry ,Organic Chemistry ,General Medicine ,Diamines ,Cell Line ,Rats ,Rats, Sprague-Dawley ,chemistry.chemical_compound ,chemistry ,Blood-Brain Barrier ,Drug Discovery ,Thiophene ,Animals ,Humans ,Receptors, Histamine H3 ,Histamine H3 receptor ,Isoxazole ,Thiazole ,H3 receptor antagonist ,Histamine H3 Antagonists ,Protein Binding ,Pyrrole ,Oxazole - Abstract
A series of small molecules consisting of a heterocyclic core flanked by two basic functionalities were synthesized and screened for in vitro affinity at the human histamine H 3 receptor (hH 3 R). Nine of the twenty-eight compounds tested were found to possess a hH 3 R K i of less than 5 nM and consisted of a diverse range of central hetero-aromatic linkers (pyridine, pyrazine, oxazole, isoxazole, thiazole, furan, thiophene, and pyrrole). One member of this series, (4-isopropyl-piperazin-1-yl)-(6-piperidin-1-ylmethyl-pyridin-3-yl)-methanone ( 37 ), was found to be a high affinity, selective antagonist that crosses the blood-brain barrier and occupies H 3 receptors after oral administration in the rat.
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- 2009
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5. Novel imidazole-based histamine H3 antagonists
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Lisa Dvorak, Curt A. Dvorak, Curt Mazur, Kiev S. Ly, Michael Bogenstaetter, Jill A. Jablonowski, Brian Lord, Timothy W. Lovenberg, Jamin D. Boggs, Kirsten L. Miller, Nicholas I. Carruthers, and Sandy J. Wilson
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Stereochemistry ,Chemistry, Pharmaceutical ,Guinea Pigs ,Clinical Biochemistry ,Drug Evaluation, Preclinical ,Pharmaceutical Science ,Ligands ,Biochemistry ,Chemical synthesis ,Structure-Activity Relationship ,chemistry.chemical_compound ,In vivo ,Biogenic amine ,Drug Discovery ,Animals ,Humans ,Imidazole ,Molecular Biology ,chemistry.chemical_classification ,Organic Chemistry ,Imidazoles ,Antagonist ,Brain ,In vitro ,Rats ,Models, Chemical ,chemistry ,Blood-Brain Barrier ,Drug Design ,Molecular Medicine ,Histamine H3 receptor ,Histamine ,Histamine H3 Antagonists ,Protein Binding - Abstract
A novel series of imidazole containing histamine H3 receptor ligands were investigated and found to be potent functional antagonists. After improving the stability of these molecules towards liver microsomes, these compounds were found to have no appreciable affinity for CYP P450s. Subsequent in vivo experiments showed significant brain uptake of (4-chloro-phenyl)-[2-(1-isopropyl-piperidin-4-ylmethoxy)-3-methyl-3H-imidazol-4-yl]-methanone 22.
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- 2009
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6. Synthesis and biological activity of piperazine and diazepane amides that are histamine H3 antagonists and serotonin reuptake inhibitors
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Xiaohui Jiang, Kirsten L. Miller, Emily M. Stocking, Lisa Dvorak, Nicholas I. Carruthers, Jamin D. Boggs, Kiev S. Ly, Sandy J. Wilson, Brian Lord, Michael A. Letavic, Diane Nepomuceno, Jennifer M. Miller, John M. Keith, Pascal Bonaventure, and Ann J. Barbier
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Serotonin reuptake inhibitor ,Clinical Biochemistry ,Pharmaceutical Science ,Pharmacology ,Biochemistry ,Chemical synthesis ,Piperazines ,Structure-Activity Relationship ,chemistry.chemical_compound ,Drug Discovery ,Animals ,Humans ,Neurotransmitter ,Molecular Biology ,Organic Chemistry ,Brain ,Biological activity ,Azepines ,Amides ,Rats ,Piperazine ,chemistry ,Molecular Medicine ,Serotonin ,Reuptake inhibitor ,Selective Serotonin Reuptake Inhibitors ,Histamine ,Histamine H3 Antagonists - Abstract
The synthesis and biological activity of a new series of piperazine and diazepane amides is described. The new compounds are high affinity histamine H 3 ligands and serotonin reuptake inhibitors.
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- 2008
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7. Novel tetrahydropyrido[3,2-c]pyrroles as 5-HT(7) antagonists
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Timothy W. Lovenberg, Dale A. Rudolph, Diane Nepomuceno, Curt A. Dvorak, Nicholas I. Carruthers, Lisa Dvorak, and Pascal Bonaventure
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Stereochemistry ,Aryl ,Organic Chemistry ,Clinical Biochemistry ,Pharmaceutical Science ,Ring (chemistry) ,Biochemistry ,Rats ,Para position ,chemistry.chemical_compound ,Structure-Activity Relationship ,chemistry ,Receptors, Serotonin ,Drug Discovery ,Molecular Medicine ,Animals ,Amine gas treating ,Pyrroles ,Serotonin Antagonists ,Receptor ,Molecular Biology ,Protein Binding - Abstract
The synthesis and SAR for a novel series of tetrahydropyrido[3,2-c]pyrroles is described. Optimization of the pendant aryl ring lead to high binding affinity at the 5-HT7 receptor when small lipophilic groups were placed in the para position. Modification of the N-benzyl group and secondary amine were not well tolerated. A representative set of compounds was shown to be functional antagonists of the 5-HT7 receptor.
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- 2010
8. Diamine-based human histamine H3 receptor antagonists: (4-aminobutyn-1-yl)benzylamines
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Curt A. Dvorak, Richard Apodaca, Pascal Bonaventure, Kirsten L. Miller, Christine Dugovic, Lisa Dvorak, Jonathan Shelton, Wei Xiao, Jill A. Jablonowski, Brian Lord, Timothy W. Lovenberg, and Nicholas I. Carruthers
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Male ,Benzylamines ,Tertiary amine ,Stereochemistry ,Diamines ,Chemical synthesis ,Cell Line ,Rats, Sprague-Dawley ,chemistry.chemical_compound ,Structure-Activity Relationship ,Benzylamine ,Diamine ,Drug Discovery ,Moiety ,Animals ,Humans ,Receptors, Histamine H3 ,Wakefulness ,Pharmacology ,Organic Chemistry ,General Medicine ,Rats ,chemistry ,Amine gas treating ,Histamine H3 receptor ,Sleep ,Histamine ,Histamine H3 Antagonists ,Protein Binding - Abstract
A series of (4-aminobutyn-1-yl)benzylamines were prepared and the SAR around three key areas: (1) the amine attached to the butynyl linker (R(3)R(4)N-); (2) the benzylamine moiety (R(1)R(2)N-); and (3) the point of attachment of the benzylamine group (R(1)R(2)N- in the ortho, meta, or para positions) was examined. One compound, 4-[3-(4-piperidin-1-yl-but-1-ynyl)-benzyl]-morpholine (9s) was chosen for further profiling and found to be a selective histamine H(3) antagonist with desirable drug-like properties. Ex vivo receptor occupancy studies established that 9s does occupy H(3) binding sites in the brain of rats after oral administration. Subcutaneous doses of 9s (10mg/kg) given during the natural sleep phase demonstrated robust wake-promoting effects.
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- 2009
9. 2-Alkyl-4-aryl-pyrimidine fused heterocycles as selective 5-HT2A antagonists
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Dale A. Rudolph, Curt A. Dvorak, Brock T. Shireman, Timothy W. Lovenberg, Nicholas I. Carruthers, Diane Nepomuceno, Pascal Bonaventure, Lisa Dvorak, and Kirsten L. Miller
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Pyrimidine ,Stereochemistry ,Clinical Biochemistry ,Pharmaceutical Science ,CHO Cells ,Biochemistry ,Chemical synthesis ,Binding, Competitive ,chemistry.chemical_compound ,Mice ,Radioligand Assay ,Structure-Activity Relationship ,Cricetulus ,Cricetinae ,Drug Discovery ,Receptor, Serotonin, 5-HT2B ,Serotonin 5-HT2 Receptor Antagonists ,Receptor, Serotonin, 5-HT2C ,Structure–activity relationship ,Animals ,Humans ,Receptor, Serotonin, 5-HT2A ,Serotonin Antagonists ,Molecular Biology ,Alkyl ,chemistry.chemical_classification ,Molecular Structure ,Aryl ,Organic Chemistry ,Azepines ,Pyrimidines ,chemistry ,NIH 3T3 Cells ,Molecular Medicine ,Selectivity - Abstract
The synthesis and SAR for a novel series of 2-alkyl-4-aryl-tetrahydro-pyrido-pyrimidines and 2-alkyl-4-aryl-tetrahydro-pyrimido-azepines is described. Representative compounds were shown to be subtype selective 5-HT(2A) antagonists. Optimal placement of a basic nitrogen relative to the pyrimidine and the presence of a 4-fluorophenyl group in the pyrimidine 4-position was found to have a profound effect on affinity and selectivity.
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- 2007
10. Lead identification of acetylcholinesterase inhibitors-histamine H3 receptor antagonists from molecular modeling
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Kirsten L. Miller, Scott D. Bembenek, Leah Aluisio, Nicholas I. Carruthers, Richard Apodaca, Timothy W. Lovenberg, Lisa Dvorak, Ann J. Barbier, Michael A. Letavic, and John M. Keith
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Models, Molecular ,medicine.drug_class ,Clinical Biochemistry ,Drug Evaluation, Preclinical ,Pharmaceutical Science ,Quantitative Structure-Activity Relationship ,Pharmacology ,Biochemistry ,chemistry.chemical_compound ,Alzheimer Disease ,Drug Discovery ,medicine ,Humans ,Receptor ,Molecular Biology ,biology ,Chemistry ,Organic Chemistry ,Antagonist ,Receptor antagonist ,Symptomatic relief ,Acetylcholinesterase ,Enzyme inhibitor ,biology.protein ,Molecular Medicine ,Cholinesterase Inhibitors ,Histamine H3 receptor ,Histamine ,Histamine H3 Antagonists - Abstract
Currently, the only clinically effective treatment for Alzheimer's disease (AD) is the use of acetylcholinesterase (AChE) inhibitors. These inhibitors have limited efficacy in that they only treat the symptoms and not the disease itself. Additionally, they often have unpleasant side effects. Here we consider the viability of a single molecule having the actions of both an AChE inhibitor and histamine H(3) receptor antagonist. Both histamine H(3) receptor antagonists and AChE inhibitors improve and augment cholinergic neurotransmission in the cortex. However, whereas an AChE inhibitor will impart its effect everywhere, a histamine H(3) antagonist will raise acetylcholine levels mostly in the brain as its mode of action will primarily be on the central nervous system. Therefore, the combination of both activities in a single molecule could be advantageous. Indeed, studies suggest an appropriate dual-acting compound may offer the desired therapeutic effect with fewer unpleasant side effects [CNS Drugs2004, 18, 827]. Further, recent studies(2) indicate the peripheral anionic site (PAS) of AChE interacts with the beta-amyloid (betaA) peptide. Consequently, a molecule capable of disrupting this interaction may have a significant impact on the production of or the aggregation of betaA. This may result in slowing down the progression of the disease rather than only treating the symptoms as current therapies do. Here, we detail how the use of the available crystal structure information, pharmacophore modeling and docking (automated, manual, classical, and QM/MM) lead to the identification of an AChE inhibitor-histamine H(3) receptor antagonist. Further, based on our models we speculate that this dual-acting compound may interact with the PAS. Such a dual-acting compound may be able to affect the pathology of AD in addition to providing symptomatic relief.
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- 2007
11. Corrigendum to '2-Alkyl-4-aryl-pyrimidine fused heterocycles as selective 5-HT2A antagonists' [Bioorg. Med. Chem. Lett. 18 (2008) 2103–2108]
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Lisa Dvorak, Diane Nepomuceno, Pascal Bonaventure, Curt A. Dvorak, Nicholas I. Carruthers, Dale A. Rudolph, Kirsten L. Miller, Timothy W. Lovenberg, and Brock T. Shireman
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chemistry.chemical_classification ,Pyrimidine ,Chemistry ,Stereochemistry ,Aryl ,Organic Chemistry ,Clinical Biochemistry ,Pharmaceutical Science ,Biochemistry ,chemistry.chemical_compound ,Drug Discovery ,Molecular Medicine ,Molecular Biology ,Alkyl - Published
- 2008
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