title: Non-basic azolotriazinone MCHR1 antagonists for the treatment of obesity: An empirical brain-exposures-driven candidate selection for in vivo efficacy studies.
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.
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: James
authors.initials: J
authors.lastname: Mignone
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: Sridhar
authors.initials: S
authors.lastname: Radhakrishnan
authors.affiliation: BMS-Biocon Research Center, Biocon, 20th KM, Hosur Road, Electronic City, Bangalore 560 100, India.
authors.forename: Jayanthi
authors.initials: J
authors.lastname: Dhanapal
authors.affiliation: BMS-Biocon Research Center, Biocon, 20th KM, Hosur Road, Electronic City, Bangalore 560 100, India.
authors.forename: Jagannath
authors.initials: J
authors.lastname: Selvaraj
authors.affiliation: BMS-Biocon Research Center, Biocon, 20th KM, Hosur Road, Electronic City, Bangalore 560 100, India.
authors.forename: Rajesh
authors.initials: R
authors.lastname: Kuppusamy
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: Metabolic Diseases Biology, Bristol-Myers Squibb Research and Development, Princeton, NJ 08543-5400, United States.
authors.forename: Paul
authors.initials: P
authors.lastname: Stetsko
authors.affiliation: Metabolic Diseases Biology, Bristol-Myers Squibb Research and Development, Princeton, NJ 08543-5400, United States.
authors.forename: Mary
authors.initials: M
authors.lastname: Grubb
authors.affiliation: Metabolic Diseases Biology, Bristol-Myers Squibb Research and Development, Princeton, NJ 08543-5400, United States.
authors.forename: Christine
authors.initials: C
authors.lastname: Huang
authors.affiliation: Metabolic Diseases Biology, Bristol-Myers Squibb Research and Development, Princeton, NJ 08543-5400, United States.
authors.forename: Lisa
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Metabolic Diseases Biology, Bristol-Myers Squibb Research and Development, Princeton, NJ 08543-5400, United States.
authors.forename: Chris
authors.initials: C
authors.lastname: Freeden
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; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006801:Humans; D015394:Molecular Structure; D009765:Obesity / Q000188:drug therapy* / Q000378:metabolism; D051381:Rats; D017481:Receptors, Somatostatin / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D014227:Triazines / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*
chemical_list: C103263:MCHR1 protein, human; D017481:Receptors, Somatostatin; D014227:Triazines; C000606690:azolotriazinone
keywords: Anti-obesity; Biliary toxicity; Metabolite toxicity; Non-basic MCHR1 antagonists; Off-rates