Orally Active Trifluoromethyl Ketone Inhibitors of Human Leukocyte Elastase

详细信息    查看全文

• 作者：Chris A. Veale ; Peter R. Bernstein ; Claudia M. Bohnert ; Frederick J. Brown ; Craig Bryant ; James R. Damewood ; Jr. ; Roger Earley ; Scott W. Feeney ; Philip D. Edwards ; Bruce Gomes ; James M. Hulsizer ; Ben
• 刊名：Journal of Medicinal Chemistry
• 出版年：1997
• 出版时间：September 26, 1997
• 年：1997
• 卷：40
• 期：20
• 页码：3173 - 3181
• 全文大小：307K
• 年卷期：v.40,no.20(September 26, 1997)
• ISSN：1520-4804

文摘

This paper describes the development a series ofpeptidyl trifluoromethyl ketone inhibitors ofhuman leukocyte elastase which are found to have excellentpharmacological profiles. Methodshave been developed that allow for the synthesis of these inhibitors instereochemically pureform. Two of these compounds, 1k and 1l,have high levels of oral bioavailability in severalspecies. Compound 1l has entered development as ZD8321and is presently undergoing clinicalevaluation. These compounds demonstrate that peptidyltrifluoromethyl ketone inhibitors canachieve high levels of oral activity and bioavailability, and thereforethey may prove useful astherapeutic agents in the treatment of diseases in which elastase isimplicated.