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

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. Graphic