Synthesis and biological evaluation of N-mercaptoacylproline and N-mercaptoacylthiazolidine-4-carboxylic acid derivatives as leukotriene A4 hydrolase inhibitors

We studied the synthetic modification of structurally similar N-mercaptoacyl-L-proline and (4R)-N-mercaptoacylthiazolidine-4-carboxylic acid to obtain potent leukotriene A(4) (LTA(4)) hydrolase inhibitors. An N-mercaptoacyl group, (2S)-3-mercapto-2-methylpropionyl group, was effective for both scaffolds. Additional introduction of a large substituent such as 4-isopropylbenzylthio (3f), 4-tert-butylbenzylthio (31) or 4-cyclohexylbenzylthio group (3m) with (S)-configuration at the C-4 position of proline yielded much more potent LTA(4) hydrolase inhibitors (IC50; 52, 31, and 34 nM, respectively) than captopril (IC50; 630,000 nM). (c) 2008 Elsevier Ltd. All rights reserved.