Identification of a Potent, Selective, and Orally Active Leukotriene A4 Hydrolase Inhibitor with Anti-Inflammatory Activity.
作者
Grice, Cheryl A.;Tays, Kevin L.;Savall, Brad M.;Wei, Jianmei;Butler, Christopher R.;Axe, Frank U.;Bembenek, Scott D.;Fourie, Anne M.;Dunford, Paul J.;Lundeen, Katherine;Coles, Fawn;Xue, Xiaohua;Riley, Jason P.;Williams, Kacy N.;Karlsson, Lars;Edwards, Jam
[摘要]：enzyme with both hydrolase and aminopeptidase activity. As a hydrolase, LTA4H stereospecifically catalyzes the transformation of the unstable epoxide LTA4 to the diol LTB4, a potent chemoattractant and activator of neutrophils and a chemoattractant of eosinophils, macrophages, mast cells, and T cells. Inhibiting the formation of LTB4 is expected to be beneficial in the treatment of inflammatory diseases such as inflammatory bowel disease (IBD), asthma, and atherosclerosis. The authors developed a pharmacophore model using a known inhibitor manually docked into the active site of LTA4H to identify a subset of compds. for screening. From this work the authors identified a series of benzoxazole, benzothiazole, and benzimidazole inhibitors. SAR studies resulted in the identification of several potent inhibitors with an appropriate cross-reactivity profile and excellent PK/PD properties. The efforts focused on further profiling JNJ 27265732, which showed encouraging efficacy in a disease model relevant to IBD.
