Synthesis and biological evaluation of N-mercaptoacylcysteine derivatives as leukotriene A4 hydrolase inhibitors |
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Authors: | Hiroshi Enomoto Yuko Morikawa Yurika Miyake Fumio Tsuji Maki Mizuchi Hiroshi Suhara Ken-ichi Fujimura Masato Horiuchi Masakazu Ban |
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Institution: | Nara Research & Development Center, Santen Pharmaceutical Co., Ltd, 8916-16 Takayama-cho, Ikoma-shi, Nara 630-0101, Japan |
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Abstract: | 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. |
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