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

We studied synthetic modifications of N-mercaptoacylamino acid derivatives to develop a new class of leukotriene A4 (LTA4) hydrolase inhibitors. S-(4-Dimethylamino)benzyl-l-cysteine derivative 2a (SA6541) showed inhibitory activity against LTA4 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 LTA4 hydrolase inhibitors.

Graphical abstractThe design, synthesis, and biological evaluation of a new class of N-mercaptoacyl-l-cysteine derivatives as leukotriene A4 (LTA4) hydrolase inhibitors are reported. Modification at the para-substituent of the phenyl ring of S-benzyl-l-cysteine moiety improved LTA4 hydrolase inhibitory activity as well as selectivity over ACE. In particular, compounds 11l and 16i having cyclohexyl group exhibited superior features about the two enzymes.Figure optionsDownload full-size imageDownload as PowerPoint slide