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

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).

• Authors: 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
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 57 Issue 18 Pg. 7509-22 (Sep 25 2014) ISSN: 1520-4804 [Electronic] United States
• PMID: 25165888 (Publication Type: Journal Article)

Chemical References

• Anti-Obesity Agents
• ERG1 Potassium Channel
• Ether-A-Go-Go Potassium Channels
• KCNH2 protein, human
• MCHR1 protein, human
• Receptors, Somatostatin

Topics

• Animals
• Anti-Obesity Agents (pharmacokinetics, pharmacology, therapeutic use)
• Dogs
• Drug Discovery
• ERG1 Potassium Channel
• Ether-A-Go-Go Potassium Channels (antagonists & inhibitors)
• Humans
• Male
• Obesity (drug therapy)
• Rats
• Receptors, Somatostatin (antagonists & inhibitors)