Synthesis and biological evaluation of N-mercaptoacylcysteine derivatives as leukotriene A 4 hydrolase inhibitors

Abstract

We studied synthetic modifications of N-mercaptoacylamino acid derivatives to develop a new class of leukotriene A 4 (LTA 4) hydrolase inhibitors. S-(4-Dimethylamino)benzyl- l-cysteine derivative 2a (SA6541) showed inhibitory activity against LTA 4 hydrolase (IC 50, 270 nM) and selectivity over other metallopeptidases except angiotensin-converting enzyme (ACE, IC 50, 520 nM). Modification at the para-substituent of the phenyl ring of compound 2a improved LTA 4 hydrolase inhibitory activity as well as selectivity over ACE. Finally, we obtained S-(4-cyclohexyl)benzy- l-cysteine derivatives 11l and 16i as potent and selective LTA 4 hydrolase inhibitors.