Synthesis and biological evaluation of N-mercaptoacylcysteine derivatives as leukotriene A4 hydrolase inhibitors

We studied synthetic modi. cations 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 (IC50, 270 nM) and selectivity over other metallopeptidases except angiotensin-converting enzyme (ACE, IC50, 520 nM). Modification at the para-substituent of the phenyl ring of compound 2a improved LTA4 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. (C) 2008 Elsevier Ltd. All rights reserved.