2. Academic Validation
  3. Identification of a nonbasic melanin hormone receptor 1 antagonist as an antiobesity clinical candidate

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

Affiliation

  • 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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