Journal article
Non-basic azolotriazinone MCHR1 antagonists for the treatment of obesity: An empirical brain-exposures-driven candidate selection for in vivo efficacy studies
Bioorganic & medicinal chemistry letters, v 25(20), pp 4412-4418
15 Oct 2015
PMID: 26386604
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Non-basic azolotriazinones were explored using an empirical free brain exposures-driven approach to identify potent MCHR1 antagonists for evaluation in in vivo efficacy studies. An optimized lead from this series, 1j (rMCHR1 Ki=1.8 nM), demonstrated a 6.9% reduction in weight gain relative to vehicle in a rat model at 30 mg/kg after 4 days of once-daily oral treatment as a glycine prodrug. Despite a promising efficacy profile, an assessment of the biliary toxicity risk of this compound rendered this compound non-progressible.
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Details
- Title
- Non-basic azolotriazinone MCHR1 antagonists for the treatment of obesity: An empirical brain-exposures-driven candidate selection for in vivo efficacy studies
- Creators
- Pratik Devasthale - Bristol-Myers Squibb (United States)Wei Wang - Bristol-Myers Squibb (United States)James Mignone - Bristol-Myers Squibb (United States)Kishore Renduchintala - Biocon (Switzerland)Sridhar Radhakrishnan - Biocon (Switzerland)Jayanthi Dhanapal - Biocon (Switzerland)Jagannath Selvaraj - Biocon (Switzerland)Rajesh Kuppusamy - Biocon (Switzerland)Mary Ann Pelleymounter - Bristol-Myers Squibb (United States)Daniel Longhi - Bristol-Myers Squibb (United States)Ning Huang - Bristol-Myers Squibb (Germany)Neil Flynn - Bristol-Myers Squibb (United States)Anthony V Azzara - Bristol-Myers Squibb (United States)Kenneth Rohrbach - Bristol-Myers Squibb (United States)James Devenny - Bristol-Myers Squibb (United States)Suzanne Rooney - Bristol-Myers Squibb (United States)Michael Thomas - Bristol-Myers Squibb (United States)Susan Glick - Bristol-Myers Squibb (United States)Helen Godonis - Bristol-Myers Squibb (United States)Susan Harvey - Bristol-Myers Squibb (United States)Mary Jane Cullen - Bristol-Myers Squibb (United States)Hongwei Zhang - Bristol-Myers Squibb (United States)Christian Caporuscio - Bristol-Myers Squibb (Germany)Paul Stetsko - Bristol-Myers Squibb (United States)Mary Grubb - Bristol-Myers Squibb (Germany)Christine Huang - Bristol-Myers Squibb (United States)Lisa Zhang - Bristol-Myers Squibb (United States)Chris Freeden - Bristol-Myers Squibb (Germany)Brian J Murphy - Bristol-Myers Squibb (United States)Jeffrey A Robl - Bristol-Myers Squibb (United States)William N Washburn - Bristol-Myers Squibb (United States)
- Publication Details
- Bioorganic & medicinal chemistry letters, v 25(20), pp 4412-4418
- Publisher
- Elsevier
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Pharmacology and Physiology
- Web of Science ID
- WOS:000362102200008
- Scopus ID
- 2-s2.0-84942828325
- Other Identifier
- 991021903123604721
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- Collaboration types
- Industry collaboration
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Chemistry, Medicinal
- Chemistry, Organic