| Discovery and biological evaluation of a novel class of dual microsomal prostaglandin E2 synthase-1/5-lipoxygenase inhibitors based on 2-[(4,6-diphenethoxypyrimidin-2-yl)thio]hexanoic acid. | |
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MedLine Citation:
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PMID: 21591611 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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Various inflammatory diseases are associated with the excessive formation of leukotrienes (LTs) and prostaglandins (PGs). Herein, we present a novel class of dual inhibitors of 5-lipoxygenase (5-LO) and microsomal prostaglandin E2 synthase-1 (mPGES-1), key enzymes in the formation of LTs and PGE2, respectively. Based on the structure of 2-[(4,6-diphenethoxypyrimidin-2-yl)thio]hexanoic acid (1) we performed a detailed SAR analysis, and mechanistic studies were carried out to elucidate the mode of 5-LO inhibition. Interestingly, the pyrimidine ring including the thioether of 1 could be replaced by a simple benzyl or a benzylidene moiety yielding novel series of bioactive 2-benzylidene- and 2-benzylhexanoic acids exemplified by 2-(2,3-diphenethoxybenzylidene)hexanoic acid 29 (IC50 5-LO = 0.8 µM; mPGES-1 = 1.1 µM). Importantly, none of the novel bioactive derivatives strongly inhibited cyclooxygenase activities. Together, we provide novel promising lead compounds for the treatment of inflammatory diseases valuable for further investigations in vivo. |
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Authors:
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Martina Hieke; Christine Greiner; Michaela Dittrich; Felix Reisen; Gisbert Schneider; Manfred Schubert-Zsilavecz; Oliver Werz |
Publication Detail:
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Type: JOURNAL ARTICLE Date: 2011-5-18 |
Journal Detail:
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Title: Journal of medicinal chemistry Volume: - ISSN: 1520-4804 ISO Abbreviation: - Publication Date: 2011 May |
Date Detail:
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Created Date: 2011-5-19 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 9716531 Medline TA: J Med Chem Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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