Synthesis and biological evaluation of N-mercaptoacylproline and N-mercaptoacylthiazolidine-4-carboxylic acid derivatives as leukotriene A4 hydrolase inhibitors |
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Authors: | Enomoto Hiroshi Morikawa Yuko Miyake Yurika Tsuji Fumio Mizuchi Maki Suhara Hiroshi Fujimura Ken-ichi Horiuchi Masato Ban Masakazu |
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Institution: | Nara Research & Development Center, Santen Pharmaceutical Co., Ltd, 8916-16, Takayama-cho, Ikoma-shi, Nara 630-0101, Japan. hiroshi.enomoto@santen.co.jp |
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Abstract: | 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 (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). |
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