Improving the developability profile of pyrrolidine progesterone receptor partial agonists

Journal Article · Fri Sep 17 04:00:00 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: Advanced Photon Source (APS), Argonne National Laboratory (ANL), Argonne, IL (US)
• Sponsoring Organization: USDOE
• OSTI ID: 1002633
• Journal Information: Bioorg. Med. Chem. Lett., Journal Name: Bioorg. Med. Chem. Lett. Journal Issue: (1) ; 01, 2010 Vol. 20; ISSN 0960-894X
• Country of Publication: United States
• Language: ENGLISH

Related Subjects

59 BASIC BIOLOGICAL SCIENCES
99 GENERAL AND MISCELLANEOUS
BIOLOGICAL FUNCTIONS
BIOLOGICAL MODELS
IN VIVO
PROGESTERONE
PYRROLIDINES
RECEPTORS
UTERUS