Title of article :
4-Aminophenylalanine and 4-aminocyclohexylalanine derivatives as potent, selective, and orally bioavailable inhibitors of dipeptidyl peptidase IV
Author/Authors :
Joseph L. Duffy، نويسنده , , Brian A. Kirk، نويسنده , , Liping Wang، نويسنده , , George J. Eiermann، نويسنده , , Huaibing He، نويسنده , , Barbara Leiting، نويسنده , , Kathryn A. Lyons، نويسنده , , Reshma A. Patel، نويسنده , , Sangita B. Patel، نويسنده , , Alexsandr Petrov، نويسنده , , Giovanna Scapin، نويسنده , , Joseph K. Wu، نويسنده , , Nancy A. Thornberry، نويسنده , , Ann E. Weber، نويسنده ,
Abstract :
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.
Keywords :
Dipeptidyl peptidase IV , Buchwald amidation , DPP-4 , Kazmaier Claisen , x-ray
