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Identification of 2-mercaptohexanoic acids as dual inhibitors of 5-lipoxygenase and microsomal prostaglandin E(2) synthase-1.
MedLine Citation:
PMID:  21570310     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
5-Lipoxygenase (5-LO) and microsomal prostaglandin E(2) synthase (mPGES)-1 are key enzymes in the biosynthesis of leukotrienes and prostaglandin (PG)E(2), respectively, and are considered as valuable targets for the treatment of inflammatory diseases. Here, we present the identification of 2-mercaptohexanoic acid derivatives as dual inhibitors of 5-LO and mPGES-1. The lead compound 2(4-(3-biphenyloxypropoxy)phenylthio)hexanoic acid (21) inhibits human 5-LO and mPGES-1 in cell-free assays with an IC(50)=3.5 and 2.2μM, respectively, and suppresses 5-LO in intact cells with even a higher potency (IC(50)=0.9μM). Compound 21 (10μM) neither significantly inhibited the related 12- or 15-LOs nor cyclooxygenase-1 and -2 or cytosolic phospholipase A(2). Based on the selective and potent inhibition of 5-LO and mPGES-1, further assessment of these 2-mercaptohexanoic acids in preclinical models of inflammation are warranted.
Authors:
Christine Greiner; Heiko Zettl; Andreas Koeberle; Carlo Pergola; Hinnak Northoff; Manfred Schubert-Zsilavecz; Oliver Werz
Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2011-4-22
Journal Detail:
Title:  Bioorganic & medicinal chemistry     Volume:  -     ISSN:  1464-3391     ISO Abbreviation:  -     Publication Date:  2011 Apr 
Date Detail:
Created Date:  2011-5-16     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9413298     Medline TA:  Bioorg Med Chem     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Copyright Information:
Copyright © 2011. Published by Elsevier Ltd.
Affiliation:
Department of Pharmaceutical Analytics, Pharmaceutical Institute, Eberhard Karls University Tuebingen, Auf der Morgenstelle 8, D-72076 Tuebingen, Germany.
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