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Improving the developability profile of pyrrolidine progesterone receptor partial agonists |
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| 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 |
| Institution: | 1. Department of Chemistry, Metabolic Pathways Centre for Excellence in Drug Discovery, GlaxoSmithKline Pharmaceuticals, 709 Swedeland Road, King of Prussia, PA 19406, USA;2. Department of Biology, Metabolic Pathways Centre for Excellence in Drug Discovery, GlaxoSmithKline Pharmaceuticals, 709 Swedeland Road, King of Prussia, PA 19406, USA;3. Department of Drug Metabolism and Pharmacokinetics, Metabolic Pathways Centre for Excellence in Drug Discovery, GlaxoSmithKline Pharmaceuticals, 709 Swedeland Road, King of Prussia, PA 19406, USA;4. Deparmtent of Computational and Structural Chemistry, Molecular Discovery Research, GlaxoSmithKline Pharmaceuticals, P.O. Box 13398, Research Triangle Park, NC 27709, USA |
| 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. |
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