Improving the developability profile of pyrrolidine progesterone receptor partial agonists

Journal Article · Fri Sep 17 00:00:00 EDT 2010 · Bioorg. Med. Chem. Lett.

DOI:https://doi.org/10.1016/j.bmcl.2009.10.092· OSTI ID:1002633

Kallander, Lara S; Washburn, David G; Hoang, Tram H; Frazee, James S; Stoy, Patrick; Johnson, Latisha; Lu, Qing; Hammond, Marlys; Barton, Linda S; Patterson, Jaclyn R; Azzarano, Leonard M; Nagilla, Rakesh; Madauss, Kevin P; Williams, Shawn P; Stewart, Eugene L; Duraiswami, Chaya; Grygielko, Eugene T; Xu, Xiaoping; Laping, Nicholas J; Bray, Jeffrey D ; Thompson, Scott K ^[1]

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1. GSKPA

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.

• Research Organization: Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
• Sponsoring Organization: USDOE
• OSTI ID: 1002633
• Journal Information: Bioorg. Med. Chem. Lett., Vol. 20, Issue (1) ; 01, 2010; ISSN 0960-894X
• Country of Publication: United States
• Language: ENGLISH

Related Subjects

59 BASIC BIOLOGICAL SCIENCES
99 GENERAL AND MISCELLANEOUS//MATHEMATICS, COMPUTING, AND INFORMATION SCIENCE
RECEPTORS
PROGESTERONE
BIOLOGICAL FUNCTIONS
IN VIVO
PYRROLIDINES
BIOLOGICAL MODELS
UTERUS