Referenced in: none

Automatically associated channels: Kv11.1

Title: Improving the developability profile of pyrrolidine progesterone receptor partial agonists.

Authors: Lara S Kallander, David G Washburn, Tram H Hoang, James S Frazee, Patrick Stoy, Latisha Johnson, Qing Lu, Marlys Hammond, Linda S Barton, Jaclyn R Patterson, Leonard M Azzarano, Rakesh Nagilla, Kevin P Madauss, Shawn P Williams, Eugene L Stewart, Chaya Duraiswami, Eugene T Grygielko, Xiaoping Xu, Nicholas J Laping, Jeffrey D Bray, Scott K Thompson

Journal, date & volume: Bioorg. Med. Chem. Lett., 2010 Jan 1 , 20, 371-4

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/19926282

Abstract
The previously reported pyrrolidine class of progesterone receptor partial agonists demonstrated excellent potency but suffered from serious liabilities including hERG blockade and high volume of distribution in the rat. The basic pyrrolidine amine was intentionally converted to a sulfonamide, carbamate, or amide to address these liabilities. The evaluation of the degree of partial agonism for these non-basic pyrrolidine derivatives and demonstration of their efficacy in an in vivo model of endometriosis is disclosed herein.