4-Aminophenylalanine and 4-aminocyclohexylalanine derivatives as potent, selective, and orally bioavailable inhibitors of dipeptidyl peptidase IV

详细信息	查看全文 | 推荐本文 |

• 作者：Joseph L. Duffy ; Brian A. Kirk ; Liping Wang ; George J. Eiermann ; Huaibing He ; Barbara Leiting ; Kathryn A. Lyons ; Reshma A. Patel ; Sangita B. Patel ; Alexs ; r Petrov ; et al.
• 关键词：Dipeptidyl peptidase IV ; DPP-4 ; Kazmaier Claisen ; Buchwald amidation ; X-ray
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2007
• 期刊代码：10_0960894x
• 类别：ch
• 出版时间：15 May 2007
• 卷：17
• 期：10
• 页码：2879-2885
• 文件大小：267 K

摘要

A novel series of 4-aminophenylalanine and 4-aminocyclohexylalanine derivatives were designed and evaluated as inhibitors of dipeptidyl peptidase IV (DPP-4). The phenylalanine series afforded compounds such as 10 that were potent and selective (DPP-4, IC₅₀ = 28 nM), but exhibited limited oral bioavailability. The corresponding cyclohexylalanine derivatives such as 25 afforded improved PK exposure and efficacy in a murine OGTT experiment. The X-ray crystal structure of 25 bound to the DPP-4 active site is presented.