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 A4 (LTA4) 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 (3l) or 4-cyclohexylbenzylthio group (3m) with (S)-configuration at the C4 position of proline yielded much more potent LTA4 hydrolase inhibitors (IC50; 52, 31, and 34 nM, respectively) than captopril (IC50; 630,000 nM).

Synthesis and leukotriene A4 (LTA4) hydrolase inhibitory activity of N-mercaptoacylproline and (4R)-N-mercaptoacylthiazolidine-4-carboxylic acid derivatives are reported. An N-mercaptoacyl group, (2S)-3-mercapto-2-methylpropionyl group, was effective for both scaffolds. Additional introduction of a substituent, such as 4-tert-butyl benzylthio, with (S)-configuration at the C4 position of proline yielded potent LTA4 hydrolase inhibitors.Figure optionsDownload as PowerPoint slide