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

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• 作者：William N. Washburn ; 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
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：September 25, 2014
• 年：2014
• 卷：57
• 期：18
• 页码：7509-7522
• 全文大小：456K
• ISSN：1520-4804

文摘

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).