| The molecular pharmacology and in vivo activity of 2-(4-chloro-6-(2,3-dimethylphenylamino)pyrimidin-2-ylthio)octanoic acid (YS121), a dual inhibitor of microsomal prostaglandin E2 synthase-1 and 5-lipoxygenase. | |
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MedLine Citation:
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PMID: 19934399 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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The microsomal prostaglandin E(2) synthase (mPGES)-1 is one of the terminal isoenzymes of prostaglandin (PG) E(2) biosynthesis. Pharmacological inhibitors of mPGES-1 are proposed as an alternative to nonsteroidal anti-inflammatory drugs. We recently presented the design and synthesis of a series of pirinixic acid derivatives that dually inhibit mPGES-1 and 5-lipoxygenase. Here, we investigated the mechanism of mPGES-1 inhibition, the selectivity profile, and the in vivo activity of alpha-(n-hexyl)-substituted pirinixic acid [YS121; 2-(4-chloro-6-(2,3-dimethylphenylamino)pyrimidin-2-ylthio)octanoic acid)] as a lead compound. In cell-free assays, YS121 inhibited human mPGES-1 in a reversible and noncompetitive manner (IC(50) = 3.4 muM), and surface plasmon resonance spectroscopy studies using purified in vitro-translated human mPGES-1 indicate direct, reversible, and specific binding to mPGES-1 (K(D) = 10-14 muM). In lipopolysaccharide-stimulated human whole blood, PGE(2) formation was concentration dependently inhibited (IC(50) = 2 muM), whereas concomitant generation of the cyclooxygenase (COX)-2-derived thromboxane B(2) and 6-keto PGF(1alpha) and the COX-1-derived 12(S)-hydroxy-5-cis-8,10-trans-heptadecatrienoic acid was not significantly reduced. In carrageenan-induced rat pleurisy, YS121 (1.5 mg/kg i.p.) blocked exudate formation and leukocyte infiltration accompanied by reduced pleural levels of PGE(2) and leukotriene B(4) but also of 6-keto PGF(1alpha). Taken together, these results indicate that YS121 is a promising inhibitor of mPGES-1 with anti-inflammatory efficiency in human whole blood as well as in vivo. |
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Authors:
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Andreas Koeberle; Antonietta Rossi; Heiko Zettl; Carlo Pergola; Friederike Dehm; Julia Bauer; Christine Greiner; Sina Reckel; Christina Hoernig; Hinnak Northoff; Frank Bernhard; Volker D?tsch; Lidia Sautebin; Manfred Schubert-Zsilavecz; Oliver Werz |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2009-11-24 |
Journal Detail:
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Title: The Journal of pharmacology and experimental therapeutics Volume: 332 ISSN: 1521-0103 ISO Abbreviation: J. Pharmacol. Exp. Ther. Publication Date: 2010 Mar |
Date Detail:
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Created Date: 2010-02-23 Completed Date: 2010-04-13 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 0376362 Medline TA: J Pharmacol Exp Ther Country: United States |
Other Details:
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Languages: eng Pagination: 840-8 Citation Subset: IM |
Affiliation:
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Department for Pharmaceutical Analytics, Pharmaceutical Institute, University of T?bingen, Auf der Morgenstelle 8, D-72076 T?bingen, Germany. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Anti-Inflammatory Agents, Non-Steroidal / pharmacology* Arachidonate 5-Lipoxygenase / antagonists & inhibitors* Carrageenan Cell Line, Tumor Humans Intramolecular Oxidoreductases / antagonists & inhibitors* Isoenzymes / antagonists & inhibitors Male Mice Microsomes / enzymology* Pleurisy / chemically induced, drug therapy, immunology Prostaglandins / biosynthesis, blood Protein Binding Pyrimidines / pharmacology* Rats Rats, Wistar Surface Plasmon Resonance |
| Chemical | |
Reg. No./Substance:
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0/2-(4-chloro-6-(2,3-dimethylphenylamino)pyrimidin-2-ylthio)octanoic acid; 0/Anti-Inflammatory Agents, Non-Steroidal; 0/Isoenzymes; 0/Prostaglandins; 0/Pyrimidines; 9000-07-1/Carrageenan; EC 1.13.11.34/Arachidonate 5-Lipoxygenase; EC 5.3.-/Intramolecular Oxidoreductases; EC 5.3.99.3/prostaglandin-E synthase |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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