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.
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.
Koeberle
Andreas
A
Department for Pharmaceutical Analytics, Pharmaceutical Institute, University of Tübingen, Auf der Morgenstelle 8, D-72076 Tübingen, Germany.
Rossi
Antonietta
A
Zettl
Heiko
H
Pergola
Carlo
C
Dehm
Friederike
F
Bauer
Julia
J
Greiner
Christine
C
Reckel
Sina
S
Hoernig
Christina
C
Northoff
Hinnak
H
Bernhard
Frank
F
Dötsch
Volker
V
Sautebin
Lidia
L
Schubert-Zsilavecz
Manfred
M
Werz
Oliver
O
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D002351:Carrageenan; D045744:Cell Line, Tumor; D006801:Humans; D019746:Intramolecular Oxidoreductases / Q000037:antagonists & inhibitors*; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D016859:Lipoxygenase Inhibitors; D008297:Male; D051379:Mice; D008861:Microsomes / Q000201:enzymology*; D010998:Pleurisy / Q000139:chemically induced / Q000188:drug therapy / Q000276:immunology; D000071876:Prostaglandin-E Synthases; D011453:Prostaglandins / Q000096:biosynthesis / Q000097:blood; D011485:Protein Binding; D011743:Pyrimidines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D020349:Surface Plasmon Resonance
C548544:2-(4-chloro-6-(2,3-dimethylphenylamino)pyrimidin-2-ylthio)octanoic acid; D000894:Anti-Inflammatory Agents, Non-Steroidal; D007527:Isoenzymes; D016859:Lipoxygenase Inhibitors; D011453:Prostaglandins; D011743:Pyrimidines; D002351:Carrageenan; D019746:Intramolecular Oxidoreductases; C000605862:PTGES protein, human; D000071876:Prostaglandin-E Synthases; C000605865:Ptges protein, mouse