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

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.

Authors:
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  1. (GSKPA)
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
USDOE
OSTI Identifier:
1002633
Resource Type:
Journal Article
Resource Relation:
Journal Name: Bioorg. Med. Chem. Lett.; Journal Volume: 20; Journal Issue: (1) ; 01, 2010
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES; 99 GENERAL AND MISCELLANEOUS//MATHEMATICS, COMPUTING, AND INFORMATION SCIENCE; RECEPTORS; PROGESTERONE; BIOLOGICAL FUNCTIONS; IN VIVO; PYRROLIDINES; BIOLOGICAL MODELS; UTERUS

Citation Formats

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., and Thompson, Scott K. Improving the developability profile of pyrrolidine progesterone receptor partial agonists. United States: N. p., 2010. Web. doi:10.1016/j.bmcl.2009.10.092.
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. Improving the developability profile of pyrrolidine progesterone receptor partial agonists. United States. doi:10.1016/j.bmcl.2009.10.092.
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., and Thompson, Scott K. Fri . "Improving the developability profile of pyrrolidine progesterone receptor partial agonists". United States. doi:10.1016/j.bmcl.2009.10.092.
@article{osti_1002633,
title = {Improving the developability profile of pyrrolidine progesterone receptor partial agonists},
author = {Kallander, Lara S. and Washburn, David G. and Hoang, Tram H. and Frazee, James S. and Stoy, Patrick and Johnson, Latisha and Lu, Qing and Hammond, Marlys and Barton, Linda S. and Patterson, Jaclyn R. and Azzarano, Leonard M. and Nagilla, Rakesh and Madauss, Kevin P. and Williams, Shawn P. and Stewart, Eugene L. and Duraiswami, Chaya and Grygielko, Eugene T. and Xu, Xiaoping and Laping, Nicholas J. and Bray, Jeffrey D. and Thompson, Scott K.},
abstractNote = {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.},
doi = {10.1016/j.bmcl.2009.10.092},
journal = {Bioorg. Med. Chem. Lett.},
number = (1) ; 01, 2010,
volume = 20,
place = {United States},
year = {Fri Sep 17 00:00:00 EDT 2010},
month = {Fri Sep 17 00:00:00 EDT 2010}
}