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Identification of a Nonbasic Melanin Hormone Receptor 1 Antagonist as an Antiobesity Clinical Candidate

2014; American Chemical Society; Volume: 57; Issue: 18 Linguagem: Inglês

10.1021/jm500026w

1520-4804

William N. Washburn, Mark C. Manfredi, Pratik Devasthale, Guohua Zhao, Saleem Ahmad, Andrés S. Hernández, Jeffrey A. Robl, Wei Wang, James Mignone, Zhenghua Wang, Khehyong Ngu, Mary Ann Pelleymounter, Daniel Angelo Longhi, Rui-Lin Zhao, Bei Wang, Ning Huang, Neil Flynn, Anthony V. Azzara, Joel C. Barrish, Kenneth W. Rohrbach, James J. Devenny, Suzanne Rooney, Michael A. Thomas, Susan Glick, Helen E. Godonis, Susan J. Harvey, Mary Jane Cullen, Hongwei Zhang, Christian Caporuscio, Paul Stetsko, Mary F. Grubb, Brad D. Maxwell, Hong Yang, Atsu Apedo, Brian Gemzik, Evan B. Janovitz, Christine Huang, Lisa Zhang, Chris Freeden, Brian J. Murphy,

Pharmacology and Obesity Treatment

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).