The reversed binding of β-phenethylamine inhibitors of DPP-IV: X-ray structures and properties of novel fragment and elaborated inhibitors

The co-crystal structure of β-phenethylamine fragment inhibitor 5 bound to DPP-IV revealed that the phenyl ring occupied the proline pocket of the enzyme. This finding provided the basis for a general hypothesis of a reverse binding mode for β-phenethylamine-based DPP-IV inhibitors. Novel inhibitor design concepts that obviate substrate-like structure–activity relationships (SAR) were thereby enabled, and novel, potent inhibitors were discovered.