Document Detail

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.
MedLine Citation:
PMID:  19934399     Owner:  NLM     Status:  MEDLINE    
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.
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:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2009-11-24
Journal Detail:
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:
Created Date:  2010-02-23     Completed Date:  2010-04-13     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0376362     Medline TA:  J Pharmacol Exp Ther     Country:  United States    
Other Details:
Languages:  eng     Pagination:  840-8     Citation Subset:  IM    
Department for Pharmaceutical Analytics, Pharmaceutical Institute, University of T?bingen, Auf der Morgenstelle 8, D-72076 T?bingen, Germany.
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MeSH Terms
Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
Arachidonate 5-Lipoxygenase / antagonists & inhibitors*
Cell Line, Tumor
Intramolecular Oxidoreductases / antagonists & inhibitors*
Isoenzymes / antagonists & inhibitors
Microsomes / enzymology*
Pleurisy / chemically induced,  drug therapy,  immunology
Prostaglandins / biosynthesis,  blood
Protein Binding
Pyrimidines / pharmacology*
Rats, Wistar
Surface Plasmon Resonance
Reg. No./Substance:
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 5-Lipoxygenase; EC 5.3.-/Intramolecular Oxidoreductases; EC synthase

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