A leukotriene C-4 synthase inhibitor with the backbone of 5-(5-methylene-4-oxo-4,5-dihydrothiazol-2-ylamino) isophthalic acid

作者：Ago Hideo^*; Okimoto Noriaki; Kanaoka Yoshihide; Morimoto Gentaro; Ukita Yoko; Saino Hiromichi; Taiji Makoto; Miyano Masashi

来源：Journal of Biochemistry, 2013, 153(5): 421-429.

DOI：10.1093/jb/mvt007

• enzyme inhibitor
• membrane protein
• leukotriene
• inflammation
• in silico screening

The cysteinyl leukotrienes (cys-LTs), leukotriene C-4 (LTC4) and its metabolites, LTD4 and LTE4, are proinflammatory lipid mediators in asthma and other inflammatory diseases. They are generated through the 5-lipoxygenase/LTC4 synthase (LTC4S) pathway and act via at least two distinct G protein-coupled receptors. The inhibition of human LTC4S will make a simple way to treat the cys-LT relevant inflammatory diseases. Here, we show that compounds having 5-(5-methylene-4-oxo-4,5-dihydrothiazol-2-ylamino) isophthalic acid moiety suppress LTC4 synthesis, glutathione conjugation to the precursor LTA(4), in both an enzyme assay and a whole-cell assay. Hierarchical in silico screenings of 6 million compounds provided 300,000 dataset for docking, and after energy minimization based on the crystal structure of LTC4S, 111 compounds were selected as candidates for a competitive inhibitor to glutathione. One of those compounds showed significant inhibitory activity, and subsequently, its derivative 5-((Z)-5-((E)-2-methyl-3-phenylallylidene)-4-oxo-4,5-dihydrothiazol-2-ylamino) isophthalic acid (compound 1) was found to be the most potent inhibitor. The enzyme assay showed the IC50 was 1.9 mu M and the corresponding 95% confidence interval was from 1.7 to 2.2 mu M. The whole-cell assay showed that compound 1 was cell permeable and inhibited LTC4 synthesis in a concentration dependent manner.

• 出版日期2013-5