Referenced in: none

Automatically associated channels: Kv11.1

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

Authors: William N Washburn, Mark Manfredi, Pratik Devasthale, Guohua Zhao, Saleem Ahmad, Andrés Hernández, 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, date & volume: J. Med. Chem., 2014 Sep 25 , 57, 7509-22

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/25165888

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).