title: Dihydropyrrolopyrazol-6-one MCHR1 antagonists for the treatment of obesity: Insights on in vivo efficacy from a novel FLIPR assay setup.
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.
authors.affiliation: Metabolic Diseases Chemistry, Bristol-Myers Squibb Research and Development, Princeton, NJ 08543-5400, United States. Electronic address: pratik.devasthale@bms.com.
authors.forename: Pratik
authors.initials: P
authors.lastname: Devasthale
authors.affiliation: Metabolic Diseases Chemistry, Bristol-Myers Squibb Research and Development, Princeton, NJ 08543-5400, United States.
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.affiliation: Metabolic Diseases Chemistry, Bristol-Myers Squibb Research and Development, Princeton, NJ 08543-5400, United States.
authors.forename: Andres S
authors.initials: AS
authors.lastname: Hernandez
authors.affiliation: Metabolic Diseases Chemistry, Bristol-Myers Squibb Research and Development, Princeton, NJ 08543-5400, United States.
authors.forename: Fang
authors.initials: F
authors.lastname: Moore
authors.affiliation: BMS-Biocon Research Center, Biocon, 20th KM, Hosur Road, Electronic City, Bangalore 560 100, India.
authors.forename: Kishore
authors.initials: K
authors.lastname: Renduchintala
authors.affiliation: BMS-Biocon Research Center, Biocon, 20th KM, Hosur Road, Electronic City, Bangalore 560 100, India.
authors.forename: Radhakrishnan
authors.initials: R
authors.lastname: Sridhar
authors.affiliation: Metabolic Diseases Biology, Bristol-Myers Squibb Research and Development, Princeton, NJ 08543-5400, United States.
authors.forename: Mary Ann
authors.initials: MA
authors.lastname: Pelleymounter
authors.affiliation: Metabolic Diseases Biology, Bristol-Myers Squibb Research and Development, Princeton, NJ 08543-5400, United States.
authors.forename: Daniel
authors.initials: D
authors.lastname: Longhi
authors.affiliation: Metabolic Diseases Biology, Bristol-Myers Squibb Research and Development, Princeton, NJ 08543-5400, United States.
authors.forename: Ning
authors.initials: N
authors.lastname: Huang
authors.affiliation: Metabolic Diseases Biology, Bristol-Myers Squibb Research and Development, Princeton, NJ 08543-5400, United States.
authors.forename: Neil
authors.initials: N
authors.lastname: Flynn
authors.affiliation: Metabolic Diseases Biology, Bristol-Myers Squibb Research and Development, Princeton, NJ 08543-5400, United States.
authors.forename: Anthony V
authors.initials: AV
authors.lastname: Azzara
authors.affiliation: Metabolic Diseases Biology, Bristol-Myers Squibb Research and Development, Princeton, NJ 08543-5400, United States.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Rohrbach
authors.affiliation: Metabolic Diseases Biology, Bristol-Myers Squibb Research and Development, Princeton, NJ 08543-5400, United States.
authors.forename: James
authors.initials: J
authors.lastname: Devenny
authors.affiliation: Metabolic Diseases Biology, Bristol-Myers Squibb Research and Development, Princeton, NJ 08543-5400, United States.
authors.forename: Suzanne
authors.initials: S
authors.lastname: Rooney
authors.affiliation: Metabolic Diseases Biology, Bristol-Myers Squibb Research and Development, Princeton, NJ 08543-5400, United States.
authors.forename: Michael
authors.initials: M
authors.lastname: Thomas
authors.affiliation: Metabolic Diseases Biology, Bristol-Myers Squibb Research and Development, Princeton, NJ 08543-5400, United States.
authors.forename: Susan
authors.initials: S
authors.lastname: Glick
authors.affiliation: Metabolic Diseases Biology, Bristol-Myers Squibb Research and Development, Princeton, NJ 08543-5400, United States.
authors.forename: Helen
authors.initials: H
authors.lastname: Godonis
authors.affiliation: Metabolic Diseases Biology, Bristol-Myers Squibb Research and Development, Princeton, NJ 08543-5400, United States.
authors.forename: Susan
authors.initials: S
authors.lastname: Harvey
authors.affiliation: Metabolic Diseases Biology, Bristol-Myers Squibb Research and Development, Princeton, NJ 08543-5400, United States.
authors.forename: Mary Jane
authors.initials: MJ
authors.lastname: Cullen
authors.affiliation: Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Research and Development, Princeton, NJ 08543-5400, United States.
authors.forename: Hongwei
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Research and Development, Princeton, NJ 08543-5400, United States.
authors.forename: Christian
authors.initials: C
authors.lastname: Caporuscio
authors.affiliation: Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Research and Development, Princeton, NJ 08543-5400, United States.
authors.forename: Paul
authors.initials: P
authors.lastname: Stetsko
authors.affiliation: Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Research and Development, Princeton, NJ 08543-5400, United States.
authors.forename: Mary
authors.initials: M
authors.lastname: Grubb
authors.affiliation: Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Research and Development, Princeton, NJ 08543-5400, United States.
authors.forename: Christine
authors.initials: C
authors.lastname: Huang
authors.affiliation: Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Research and Development, Princeton, NJ 08543-5400, United States.
authors.forename: Lisa
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Research and Development, Princeton, NJ 08543-5400, United States.
authors.forename: Chris
authors.initials: C
authors.lastname: Freeden
authors.affiliation: Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Research and Development, Princeton, NJ 08543-5400, United States.
authors.forename: Yi-Xin
authors.initials: YX
authors.lastname: Li
authors.affiliation: Metabolic Diseases Biology, Bristol-Myers Squibb Research and Development, Princeton, NJ 08543-5400, United States.
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Murphy
authors.affiliation: Metabolic Diseases Chemistry, Bristol-Myers Squibb Research and Development, Princeton, NJ 08543-5400, United States.
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Robl
authors.affiliation: Metabolic Diseases Chemistry, Bristol-Myers Squibb Research and Development, Princeton, NJ 08543-5400, United States.
authors.forename: William N
authors.initials: WN
authors.lastname: Washburn
mesh_terms: D000818:Animals; D019440:Anti-Obesity Agents / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D006207:Half-Life; D006801:Humans; D009765:Obesity / Q000188:drug therapy; D011485:Protein Binding; D011720:Pyrazoles / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D017481:Receptors, Somatostatin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D015431:Weight Loss / Q000187:drug effects
chemical_list: D019440:Anti-Obesity Agents; C103263:MCHR1 protein, human; D011720:Pyrazoles; D017481:Receptors, Somatostatin; C031280:pyrazole
keywords: Dihydropyrrolopyrazolones; MCHR1 receptor antagonists; Obesity; Off-rates