Journal of medicinal chemistry, 14 July 2011, Vol.54(13), pp.4490-507
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 E(2) synthase-1 (mPGES-1), key enzymes in the formation of LTs and PGE(2), respectively. On the basis of 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 a novel series of bioactive 2-benzylidene- and 2-benzylhexanoic acids exemplified by 2-(2,3-diphenethoxybenzylidene)hexanoic acid, 29 (IC(50) 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.
Anti-Inflammatory Agents, Non-Steroidal -- Chemical Synthesis ; Benzene Derivatives -- Chemical Synthesis ; Caproates -- Chemical Synthesis ; Intramolecular Oxidoreductases -- Antagonists & Inhibitors ; Lipoxygenase Inhibitors -- Chemical Synthesis ; Microsomes -- Enzymology ; Pyrimidines -- Chemical Synthesis
View this record in MEDLINE/PubMed