Identification of a nonbasic melanin hormone receptor 1 antagonist as an antiobesity clinical candidate

  • J Med Chem. 2014 Sep 25;57(18):7509-22. doi: 10.1021/jm500026w.
William N Washburn  1 ,  Mark Manfredi ,  Pratik Devasthale ,  Guohua Zhao ,  Saleem Ahmad ,  Andres Hernandez ,  Jeffrey A Robl ,  Wei Wang ,  James Mignone ,  Zhenghua Wang ,  Khehyong Ngu ,  Mary Ann Pelleymounter ,  Daniel Longhi ,  Rulin Zhao ,  Bei Wang ,  Ning Huang ,  Neil Flynn ,  Anthony V Azzara ,  Joel C Barrish ,  Kenneth Rohrbach ,  James J Devenny ,  Suzanne Rooney ,  Michael Thomas ,  Susan Glick ,  Helen E Godonis ,  Susan J Harvey ,  Mary Jane Cullen ,  Hongwei Zhang ,  Christian Caporuscio ,  Paul Stetsko ,  Mary Grubb ,  Brad D Maxwell ,  Hong Yang ,  Atsu Apedo ,  Brian Gemzik ,  Evan B Janovitz ,  Christine Huang ,  Lisa Zhang ,  Chris Freeden ,  Brian J Murphy
Affiliations
  • 1. 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.
PMID: 25165888 DOI: 10.1021/jm500026w
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).

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