2. Academic Validation
  3. Dihydropyrrolopyrazol-6-one MCHR1 antagonists for the treatment of obesity: Insights on in vivo efficacy from a novel FLIPR assay setup

Dihydropyrrolopyrazol-6-one MCHR1 antagonists for the treatment of obesity: Insights on in vivo efficacy from a novel FLIPR assay setup

  • Bioorg Med Chem Lett. 2015 Jul 15;25(14):2793-9. doi: 10.1016/j.bmcl.2015.05.008.
Pratik Devasthale 1,  Wei Wang 2,  Andres S Hernandez 2,  Fang Moore 2,  Kishore Renduchintala 3,  Radhakrishnan Sridhar 3,  Mary Ann Pelleymounter 4,  Daniel Longhi 4,  Ning Huang 4,  Neil Flynn 4,  Anthony V Azzara 4,  Kenneth Rohrbach 4,  James Devenny 4,  Suzanne Rooney 4,  Michael Thomas 4,  Susan Glick 4,  Helen Godonis 4,  Susan Harvey 4,  Mary Jane Cullen 4,  Hongwei Zhang 5,  Christian Caporuscio 5,  Paul Stetsko 5,  Mary Grubb 5,  Christine Huang 5,  Lisa Zhang 5,  Chris Freeden 5,  Yi-Xin Li 5,  Brian J Murphy 4,  Jeffrey A Robl 2,  William N Washburn 2
Affiliations

Affiliations

  • 1 Metabolic Diseases Chemistry, Bristol-Myers Squibb Research and Development, Princeton, NJ 08543-5400, United States. Electronic address: pratik.devasthale@bms.com.
  • 2 Metabolic Diseases Chemistry, Bristol-Myers Squibb Research and Development, Princeton, NJ 08543-5400, United States.
  • 3 BMS-Biocon Research Center, Biocon, 20th KM, Hosur Road, Electronic City, Bangalore 560 100, India.
  • 4 Metabolic Diseases Biology, Bristol-Myers Squibb Research and Development, Princeton, NJ 08543-5400, United States.
  • 5 Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Research and Development, Princeton, NJ 08543-5400, United States.
PMID: 26022839 DOI: 10.1016/j.bmcl.2015.05.008
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.

Keywords

Dihydropyrrolopyrazolones; MCHR1 receptor antagonists; Obesity; Off-rates.

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