Design and synthesis of new orally active inhibitors of human neutrophil elastase |
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Authors: | Ohmoto K Okuma M Yamamoto T Kijima H Sekioka T Kitagawa K Yamamoto S Tanaka K Kawabata K Sakata A Imawaka H Nakai H Toda M |
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Institution: | Minase Research Institute, Ono Pharmaceutical Co., Ltd., Shimamoto, Mishima, Osaka 618-8585, Japan. |
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Abstract: | To identify new orally active inhibitors, further modification of 1 (ONO-6818) was performed. Peptidic derivatives 4b, 4c and 4n showed more potent inhibitory activity than nonpeptidic derivatives 3a-c. As a result, a series of peptidic inhibitors, 4a-s and 5a-v, were discovered. Among these N-aryl derivatives 5a-g, 5i, 5m and 5o-v showed oral activity. Their oral activity showed good correlation with their metabolic stability. Compounds 5h and 5j-l, which were extremely metabolically unstable in hamster plasma, did not show oral activity. Oral activity was considered to be determined by a combination of at least two factors: oral absorption and metabolic stability. |
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