Structure Report for: 2OPH

Duffy, J.L., Kirk, B.A,, Wang, L., Eiermann, G.J., He, H., Leiting, B., Lyons, K.A., Patel, R.A., Patel, S.B. et. al, and Weber, A.E.

Title: 4-aminophenylalanine and 4-aminocyclohexylalanine derivatives as potent, selective, and orally bioavailable inhibitors of dipeptidyl peptidase IV
Duffy JL, Kirk BA, Wang L, Eiermann GJ, He H, Leiting B, Lyons KA, Patel RA, Patel SB and Weber AE <4 more author(s)> Duffy JL, Kirk BA, Wang L, Eiermann GJ, He H, Leiting B, Lyons KA, Patel RA, Patel SB, Petrov A, Scapin G, Wu JK, Thornberry NA, Weber AE (- 4)
Ref: Bioorganic & Medicinal Chemistry Lett, 17:2879, 2007 : PubMed
Abstract


ESTHER: Duffy_2007_Bioorg.Med.Chem.Lett_17_2879
PubMedSearch: Duffy 2007 Bioorg.Med.Chem.Lett 17 2879
PubMedID: 17350841
Gene_locus related to this paper: human-DPP4
Inhibitor(s) related to this paper: 4-aminocyclohexylalanine-derivative-25

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, IC(50)=28nM), 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.