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Identification of a nonbasic melanin hormone receptor 1 antagonist as an antiobesity clinical candidate
William N Washburn1, Mark Manfredi, Pratik Devasthale
1Metabolic 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.
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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