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