title: Design and synthesis of new orally active inhibitors of human neutrophil elastase.
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.
authors.affiliation: Minase Research Institute, Ono Pharmaceutical Co., Ltd., Shimamoto, Mishima, Osaka 618-8585, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Ohmoto
authors.forename: M
authors.initials: M
authors.lastname: Okuma
authors.forename: T
authors.initials: T
authors.lastname: Yamamoto
authors.forename: H
authors.initials: H
authors.lastname: Kijima
authors.forename: T
authors.initials: T
authors.lastname: Sekioka
authors.forename: K
authors.initials: K
authors.lastname: Kitagawa
authors.forename: S
authors.initials: S
authors.lastname: Yamamoto
authors.forename: K
authors.initials: K
authors.lastname: Tanaka
authors.forename: K
authors.initials: K
authors.lastname: Kawabata
authors.forename: A
authors.initials: A
authors.lastname: Sakata
authors.forename: H
authors.initials: H
authors.lastname: Imawaka
authors.forename: H
authors.initials: H
authors.lastname: Nakai
authors.forename: M
authors.initials: M
authors.lastname: Toda
mesh_terms: D000284:Administration, Oral; D000818:Animals; D006224:Cricetinae; D015195:Drug Design; D004355:Drug Stability; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D006868:Hydrolysis; D019272:Leukocyte Elastase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010069:Oxadiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D010455:Peptides / Q000138:chemical synthesis / Q000378:metabolism; D011744:Pyrimidinones / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; C419152:ONO 6818; D010069:Oxadiazoles; D010455:Peptides; D011744:Pyrimidinones; D019272:Leukocyte Elastase