title: Identification of a nonbasic melanin hormone receptor 1 antagonist as an antiobesity clinical candidate.
abstract: Identification of MCHR1 antagonists with a preclinical safety profile to support clinical evaluation as antiobesity agents has been a challenge. Our finding that a basic moiety is not required for MCHR1 antagonists to achieve high affinity allowed us to explore structures less prone to off-target activities such as hERG inhibition. We report the SAR evolution of hydroxylated thienopyrimidinone ethers culminating in the identification of 27 (BMS-819881), which entered obesity clinical trials as the phosphate ester prodrug 35 (BMS-830216).
authors.affiliation: Metabolic Diseases Chemistry, ‡Metabolic Diseases Biology, §Preclinical Candidate Optimization Metabolism and Pharmacokinetics, ∥Discovery Chemistry Synthesis, ⊥Preclinical Candidate Optimization Discovery Toxicology, #Preclinical Candidate Optimization Discovery Bioanalytical Research, ∞Preclinical Candidate Optimization Biotransformation, ×Preclinical Candidate Optimization Pharmaceutics, and ○Preclinical Candidate Optimization DAS SPS, Research and Development, Bristol-Myers Squibb Co. , Princeton, New Jersey 08543-5400, United States.
authors.forename: William N
authors.initials: WN
authors.lastname: Washburn
authors.forename: Mark
authors.initials: M
authors.lastname: Manfredi
authors.forename: Pratik
authors.initials: P
authors.lastname: Devasthale
authors.forename: Guohua
authors.initials: G
authors.lastname: Zhao
authors.forename: Saleem
authors.initials: S
authors.lastname: Ahmad
authors.forename: Andres
authors.initials: A
authors.lastname: Hernandez
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Robl
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.forename: James
authors.initials: J
authors.lastname: Mignone
authors.forename: Zhenghua
authors.initials: Z
authors.lastname: Wang
authors.forename: Khehyong
authors.initials: K
authors.lastname: Ngu
authors.forename: Mary Ann
authors.initials: MA
authors.lastname: Pelleymounter
authors.forename: Daniel
authors.initials: D
authors.lastname: Longhi
authors.forename: Rulin
authors.initials: R
authors.lastname: Zhao
authors.forename: Bei
authors.initials: B
authors.lastname: Wang
authors.forename: Ning
authors.initials: N
authors.lastname: Huang
authors.forename: Neil
authors.initials: N
authors.lastname: Flynn
authors.forename: Anthony V
authors.initials: AV
authors.lastname: Azzara
authors.forename: Joel C
authors.initials: JC
authors.lastname: Barrish
authors.forename: Kenneth
authors.initials: K
authors.lastname: Rohrbach
authors.forename: James J
authors.initials: JJ
authors.lastname: Devenny
authors.forename: Suzanne
authors.initials: S
authors.lastname: Rooney
authors.forename: Michael
authors.initials: M
authors.lastname: Thomas
authors.forename: Susan
authors.initials: S
authors.lastname: Glick
authors.forename: Helen E
authors.initials: HE
authors.lastname: Godonis
authors.forename: Susan J
authors.initials: SJ
authors.lastname: Harvey
authors.forename: Mary Jane
authors.initials: MJ
authors.lastname: Cullen
authors.forename: Hongwei
authors.initials: H
authors.lastname: Zhang
authors.forename: Christian
authors.initials: C
authors.lastname: Caporuscio
authors.forename: Paul
authors.initials: P
authors.lastname: Stetsko
authors.forename: Mary
authors.initials: M
authors.lastname: Grubb
authors.forename: Brad D
authors.initials: BD
authors.lastname: Maxwell
authors.forename: Hong
authors.initials: H
authors.lastname: Yang
authors.forename: Atsu
authors.initials: A
authors.lastname: Apedo
authors.forename: Brian
authors.initials: B
authors.lastname: Gemzik
authors.forename: Evan B
authors.initials: EB
authors.lastname: Janovitz
authors.forename: Christine
authors.initials: C
authors.lastname: Huang
authors.forename: Lisa
authors.initials: L
authors.lastname: Zhang
authors.forename: Chris
authors.initials: C
authors.lastname: Freeden
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Murphy
mesh_terms: D000818:Animals; D019440:Anti-Obesity Agents / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D004285:Dogs; D055808:Drug Discovery; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors; D006801:Humans; D008297:Male; D009765:Obesity / Q000188:drug therapy*; D051381:Rats; D017481:Receptors, Somatostatin / Q000037:antagonists & inhibitors*
chemical_list: D019440:Anti-Obesity Agents; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; C103263:MCHR1 protein, human; D017481:Receptors, Somatostatin