2. Academic Validation
  3. Design and synthesis of new orally active inhibitors of human neutrophil elastase

Design and synthesis of new orally active inhibitors of human neutrophil elastase

  • Bioorg Med Chem. 2001 May;9(5):1307-23. doi: 10.1016/s0968-0896(01)00007-4.
K Ohmoto 1,  M Okuma,  T Yamamoto,  H Kijima,  T Sekioka,  K Kitagawa,  S Yamamoto,  K Tanaka,  K Kawabata,  A Sakata,  H Imawaka,  H Nakai,  M Toda
Affiliations

Affiliation

  • 1 Minase Research Institute, Ono Pharmaceutical Co., Ltd., Shimamoto, Mishima, Osaka 618-8585, Japan.
PMID: 11377188 DOI: 10.1016/s0968-0896(01)00007-4
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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