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10 results on '"Brian M. Mathes"'

1. Synthesis and Preclinical Characterization of LY3154885, a Human Dopamine D1 Receptor Positive Allosteric Modulator with an Improved Nonclinical Drug–Drug Interaction Risk Profile

Author

Junliang Hao, James Beck, Xin Zhou, Gregory L. Lackner, Richard Johnston, Matt Reinhard, Paul Goldsmith, Sean Hollinshead, Veronique Dehlinger, Sandra A. Filla, Xu-shan Wang, Jeffery Richardson, Maria Posada, Mike Mohutsky, Doug Schober, Jason S. Katner, Qi Chen, Bingjie Hu, David M. Remick, David A. Coates, Brian M. Mathes, Mai K. Hawk, Kjell A. Svensson, and Erik Hembre

Subjects
Neuroprotective Agents, Allosteric Regulation, Receptors, Dopamine D1, Drug Discovery, Cytochrome P-450 CYP3A, Cytochrome P-450 CYP3A Inhibitors, Humans, Molecular Medicine, Drug Interactions
Abstract

Results from recently completed clinical studies suggest the dopamine D1 receptor positive allosteric modulator (PAM) mevidalen (

Published
2022
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2. Defining Target Engagement Required for Efficacy

Author

Charles W, Lugar, Christian A, Clarke, Richard, Morphy, Helene, Rudyk, Selma, Sapmaz, Ryan E, Stites, Grant M, Vaught, Kelly, Furness, Howard B, Broughton, Greg L, Durst, David K, Clawson, Stephanie L, Stout, Sherry Y, Guo, Jim D, Durbin, Keith R, Stayrook, Denise D, Edmondson, Kristy, Kikly, Nicole E, New, Holly A, Bina, Mark G, Chambers, Pamela, Shetler, William Y, Chang, Veavi Ching-Yun, Chang, Rob, Barr, Wendy H, Gough, Jimmy P, Steele, Brian, Getman, Nita, Patel, Brian M, Mathes, and Timothy I, Richardson

Subjects
Binding Sites, Arthritis, Interleukin-17, Thiophenes, Molecular Dynamics Simulation, Nuclear Receptor Subfamily 1, Group F, Member 3, Crystallography, X-Ray, Ligands, Disease Models, Animal, Mice, Structure-Activity Relationship, Drug Design, Leukocytes, Mononuclear, Animals, Humans, Female, Half-Life, Protein Binding
Abstract

The Th17 pathway has been implicated in autoimmune diseases. The retinoic acid receptor-related orphan receptor C2 (RORγt) is a master regulator of Th17 cells and controls the expression of IL-17A. RORγt is expressed primarily in IL-17A-producing lymphoid cells. Here we describe a virtual screen of the ligand-binding pocket and subsequent screen in a binding assay that identified the 1-benzyl-4',5'-dihydrospiro[piperidine-4,7'-thieno[2,3

Published
2021

3. Discovery of selective N-[3-(1-methyl-piperidine-4-carbonyl)-phenyl]-benzamide-based 5-HT₁ F receptor agonists: Evolution from bicyclic to monocyclic cores

Author

Deyi, Zhang, Maria-Jesus, Blanco, Bai-Ping, Ying, Daniel, Kohlman, Sidney X, Liang, Frantz, Victor, Qi, Chen, Joseph, Krushinski, Sandra A, Filla, Kevin J, Hudziak, Brian M, Mathes, Michael P, Cohen, DeAnna, Zacherl, David L G, Nelson, David B, Wainscott, Suzanne E, Nutter, Wendy H, Gough, John M, Schaus, and Yao-Chang, Xu

Subjects
Structure-Activity Relationship, Dose-Response Relationship, Drug, Molecular Structure, Piperidines, Benzamides, Drug Discovery, Humans, Quantum Theory, Serotonin 5-HT1 Receptor Agonists, Receptors, Serotonin, 5-HT1
Abstract

Preclinical experiments and clinical observations suggest the potential effectiveness of selective 5-HT1F receptor agonists in migraine. Identifying compounds with enhanced selectivity is crucial to assess its therapeutic value. Replacement of the indole nucleus in 2 (LY334370) with a monocyclic phenyl ketone moiety generated potent and more selective 5-HT1F receptor agonists. Focused SAR studies around this central phenyl ring demonstrated that the electrostatic and steric interactions of the substituent with both the amide CONH group and the ketone CO group play pivotal roles in affecting the adopted conformation and thus the 5-HT1F receptor selectivity. Computational studies confirmed the observed results and provide a useful tool in the understanding of the conformational requirements for 5-HT1F receptor agonist activity and selectivity. Through this effort, the 2-F-phenyl and N-2-pyridyl series were also identified as potent and selective 5-HT1F receptor agonists.

Published
2015

4. Lithium

Author

Karin Briner, Brian M. Mathes, Diego J. Ramón, and Miguel Yus

Published
2014
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7. The Potent BACE1 Inhibitor LY2886721 Elicits Robust Central Aβ Pharmacodynamic Responses in Mice, Dogs, and Humans.

Author

May, Patrick C., Willis, Brian A., Lowe, Stephen L., Dean, Robert A., Monk, Scott A., Cocke, Patrick J., Audia, James E., Boggs, Leonard N., Borders, Anthony R., Brier, Richard A., Calligaro, David O., Day, Theresa A., Ereshefsky, Larry, Erickson, Jon A., Gevorkyan, Hykop, Gonzales, Celedón R., James, Douglas E., Jhee, Stanford S., Komjathy, Steven F., and Li, Linglin

Subjects
PROTEASE inhibitors, AMYLOID beta-protein, ALZHEIMER'S disease, CLINICAL trials, NEURODEGENERATION, MEMORY loss, DEMENTIA
Abstract

BACE1 is a key protease controlling the formation of amyloid β, a peptide hypothesized to play a significant role in the pathogenesis of Alzheimer's disease (AD). Therefore, the development of potent and selective inhibitors of BACE1 has been a focus of many drug discovery efforts in academia and industry. Herein, we report the nonclinical and early clinical development of LY2886721, a BACE1 active site inhibitor that reached phase 2 clinical trials in AD. LY2886721 has high selectivity against key off-target proteases, which efficiently translates in vitro activity into robust in vivo amyloid β lowering in nonclinical animal models. Similar potent and persistent amyloid β lowering was observed in plasma and lumbar CSF when single and multiple doses of LY2886721 were administered to healthy human subjects. Collectively, these data add support for BACE1 inhibition as an effective means of amyloid lowering and as an attractive target for potential disease modification therapy in AD. [ABSTRACT FROM AUTHOR]

Published
2015
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8. Reagents for Radical and Radical Ion Chemistry

Author

David Crich and David Crich

Subjects
Radicals (Chemistry), Chemical tests and reagents, Organic compounds--Synthesis
Abstract

Radicals and radical ions are important intermediates with wide use in organic synthesis. The first book to concentrate on reagents for the creation and use of radicals and radical ions, this new volume in the Handbooks of Reagents for Organic Synthesis series compiles articles taken from the e-eros database, on reagents for use in radical and radical chemistry, to help the chemist in the lab choose the right reagents. Reflecting the enormous growth of radical chemistry over the past ten years, this is an essential guide for all synthetic chemists.

Published
2008

9. Investigators from Eli Lilly and Company Zero in on Dopamine Receptors (Synthesis and Preclinical Characterization of Ly3154885, a Human Dopamine D1 Receptor Positive Allosteric Modulator With an Improved Nonclinical Drug-drug Interaction Risk ...)

Subjects
Eli Lilly and Co., Physiological aspects, Complications and side effects, Drug interactions -- Physiological aspects, Cytochrome P-450 -- Physiological aspects, Medical research -- Physiological aspects, Pharmaceutical industry -- Physiological aspects, Dopamine -- Complications and side effects, Dopamine receptors -- Physiological aspects, Membrane proteins -- Physiological aspects, Phenols (Class of compounds) -- Physiological aspects, Medicine, Experimental -- Physiological aspects, Phenols -- Physiological aspects
Abstract

2022 APR 18 (NewsRx) -- By a News Reporter-Staff News Editor at Clinical Trials Week -- Current study results on Membrane Proteins - Dopamine Receptors have been published. According to [...]

Published
2022

10. Recent Findings from Eli Lilly and Company Provides New Insights into Cytoplasmic and Nuclear Receptors [Defining Target Engagement Required for Efficacy In Vivo At the Retinoic Acid Receptor-related Orphan Receptor C2 (Ror Gamma T)]

Subjects
Eli Lilly and Co. -- Reports, Reports, Pharmaceutical industry -- Reports
Abstract

2021 JUN 28 (NewsRx) -- By a News Reporter-Staff News Editor at Pharma Business Week -- Research findings on Proteins - Cytoplasmic and Nuclear Receptors are discussed in a new [...]

Published
2021

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