Discovery of β-homophenylalanine based pyrrolidin-2-ylmethyl amides and sulfonamides as highly potent and selective inhibitors of dipeptidyl peptidase IV

A series of β-homophenylalanine based pyrrolidin-2-ylmethyl amides and sulfonamides was evaluated as inhibitors of DPP-4. With compound 7k one of the most potent non-covalent inhibitors of DPP-4 reported to date (IC50=0.38nM) was discovered. X-ray structure of inhibitor 7k bound to DPP-4 revealed a hydrogen bonding interaction with Q553.