Document Detail

Improving the developability profile of pyrrolidine progesterone receptor partial agonists.
MedLine Citation:
PMID:  19926282     Owner:  NLM     Status:  MEDLINE    
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.
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
Publication Detail:
Type:  Journal Article     Date:  2009-10-25
Journal Detail:
Title:  Bioorganic & medicinal chemistry letters     Volume:  20     ISSN:  1464-3405     ISO Abbreviation:  Bioorg. Med. Chem. Lett.     Publication Date:  2010 Jan 
Date Detail:
Created Date:  2010-02-03     Completed Date:  2010-05-06     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9107377     Medline TA:  Bioorg Med Chem Lett     Country:  England    
Other Details:
Languages:  eng     Pagination:  371-4     Citation Subset:  IM    
Copyright Information:
Copyright 2009 Elsevier Ltd. All rights reserved.
Department of Chemistry, Metabolic Pathways Centre for Excellence in Drug Discovery, GlaxoSmithKline Pharmaceuticals, 709 Swedeland Road, King of Prussia, PA 19406, USA.
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MeSH Terms
Binding Sites
Carbamates / chemistry
Crystallography, X-Ray
Endometriosis / drug therapy
Ether-A-Go-Go Potassium Channels / metabolism
Pyrrolidines / chemical synthesis,  chemistry*,  pharmacokinetics
Receptors, Progesterone / agonists*,  metabolism
Sulfonamides / chemistry
Reg. No./Substance:
0/Carbamates; 0/ERG1 potassium channel; 0/Ether-A-Go-Go Potassium Channels; 0/Pyrrolidines; 0/Receptors, Progesterone; 0/Sulfonamides; 123-75-1/pyrrolidine

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