Referenced in: none

Automatically associated channels: Kv11.1

Title: Novel pyrrolidine melanin-concentrating hormone receptor 1 antagonists with reduced hERG inhibition.

Authors: Brian M Fox, Reina Natero, Kevin Richard, Richard Connors, Philip M Roveto, Holger Beckmann, Katrin Haller, Justin Golde, Shou-Hua Xiao, Frank Kayser

Journal, date & volume: Bioorg. Med. Chem. Lett., 2011 Apr 15 , 21, 2460-7

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/21414780

Abstract
We discovered novel pyrrolidine MCHR1 antagonist 1 possessing moderate potency. Profiling of pyrrolidine 1 demonstrated that it was an inhibitor of the hERG channel. Investigation of the structure-activity relationship of this class of pyrrolidines allowed us to optimize the MCHR1 potency and decrease the hERG inhibition. Increasing the acidity of the amide proton by converting the benzamide in lead 1 to an anilide provided single digit nanomolar MCHR1 antagonists while replacing the dimethoxyphenyl ring of 1 with alkyl groups possessing increased polarity dramatically reduced the hERG inhibition.