Discovery of potent and selective phenylalanine based dipeptidyl peptidase IV inhibitors

Abstract Modification of in-house screening lead β-aminoacyl proline 8 gave an equipotent thiazolidide 9 . Extensive SAR studies on the phenyl ring of 9 led to the discovery of a novel series of potent and selective DP-IV inhibitors. Introduction of a fluorine at the 2-position proved to be crucial for the potency of this series. The 2,5-difluoro ( 22q ) and 2,4,5-trifluoro ( 22t ) analogues were potent inhibitors of DP-IV (IC 50  = 270, 119 nM, respectively).