1. Improving the developability profile of pyrrolidine progesterone receptor partial agonists
- Author
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Eugene T. Grygielko, Patrick Stoy, Eugene L. Stewart, Tram H. Hoang, Johnson Latisha C, Jaclyn R. Patterson, Marlys Hammond, Qing Lu, Linda S. Barton, Rakesh Nagilla, David G. Washburn, Shawn P. Williams, Lara S. Kallander, Jeffrey D. Bray, Leonard M. Azzarano, Scott K. Thompson, Chaya Duraiswami, James S. Frazee, Kevin P. Madauss, Nicholas J. Laping, and Xiaoping Xu
- Subjects
ERG1 Potassium Channel ,Pyrrolidines ,medicine.drug_class ,Stereochemistry ,Clinical Biochemistry ,hERG ,Endometriosis ,Pharmaceutical Science ,Carboxamide ,Crystallography, X-Ray ,Biochemistry ,Chemical synthesis ,Partial agonist ,Pyrrolidine ,chemistry.chemical_compound ,In vivo ,Drug Discovery ,Progesterone receptor ,medicine ,Animals ,Humans ,Receptor ,Molecular Biology ,Sulfonamides ,Binding Sites ,biology ,Chemistry ,Organic Chemistry ,Ether-A-Go-Go Potassium Channels ,Rats ,biology.protein ,Molecular Medicine ,Female ,Carbamates ,Receptors, Progesterone - 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.
- Published
- 2009