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

Abstract

We studied the synthetic modification of structurally similar N-mercaptoacyl- l-proline and (4 R)- N-mercaptoacylthiazolidine-4-carboxylic acid to obtain potent leukotriene A 4 (LTA 4) hydrolase inhibitors. An N-mercaptoacyl group, (2 S)-3-mercapto-2-methylpropionyl group, was effective for both scaffolds. Additional introduction of a large substituent such as 4-isopropylbenzylthio ( 3f), 4- tert-butylbenzylthio ( 3l) or 4-cyclohexylbenzylthio group ( 3m) with ( S)-configuration at the C 4 position of proline yielded much more potent LTA 4 hydrolase inhibitors (IC 50; 52, 31, and 34 nM, respectively) than captopril (IC 50; 630,000 nM).