Journal article
Dihydropyrrolopyrazol-6-one MCHR1 antagonists for the treatment of obesity: Insights on in vivo efficacy from a novel FLIPR assay setup
Bioorganic & medicinal chemistry letters, v 25(14), pp 2793-2799
15 Jul 2015
PMID: 26022839
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Our investigation of the structure-activity and structure-liability relationships for dihydropyrrolopyrazol-6-one MCHR1 antagonists revealed that off-rate characteristics, inferred from potencies in a FLIPR assay following a 2 h incubation, can impact in vivo efficacy. The in vitro and exposure profiles of dihydropyrrolopyrazol-6-ones 1b and 1e were comparable to that of the thienopyrimidinone counterparts 41 and 43 except for a much faster MCHR1 apparent off-rate. The greatly diminished dihydropyrrolopyrazol-6-one anti-obesity response may be the consequence of this rapid off-rate.
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Details
- Title
- Dihydropyrrolopyrazol-6-one MCHR1 antagonists for the treatment of obesity: Insights on in vivo efficacy from a novel FLIPR assay setup
- Creators
- Pratik Devasthale - Bristol-Myers Squibb (United States)Wei Wang - Bristol-Myers Squibb (United States)Andres S Hernandez - Bristol-Myers Squibb (United States)Fang Moore - Bristol-Myers Squibb (United States)Kishore Renduchintala - Biocon (Switzerland)Radhakrishnan Sridhar - Biocon (India)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)Yi-Xin Li - Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Research and Development, Princeton, NJ 08543-5400, United StatesBrian 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(14), pp 2793-2799
- Publisher
- Elsevier
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Pharmacology and Physiology
- Web of Science ID
- WOS:000355663100013
- Scopus ID
- 2-s2.0-84930274029
- Other Identifier
- 991021902524604721
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- Collaboration types
- Industry collaboration
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Chemistry, Medicinal
- Chemistry, Organic