Nonpeptide small-molecular inhibitors of dipeptidyl peptidase IV: N-phenylphthalimide analogs

Abstract A novel series of nonpeptide small-molecular dipeptidyl peptidase IV (DPP-IV) inhibitors with an N -phenylphthalimide skeleton has been developed. Some of the compounds, including 4 -amino-(2,6-dimethylphenyl)phthalimides ( 7 ), 4 - and 5-hydroxy-(2,6-diethyl-phenyl)phthalimide ( 11 and 14 ), 4 -hydroxy-(2,6-diisopropylphenyl)phthalimide ( 12 ), and thiocarbonyl analogs of (2,6-diisopropylphenyl)phthalimide and their 4 ,5, 6 ,7-tetrafluorinated derivative ( 18, 19 and 20 ), were more potent than the well-known DPP-IV-specific inhibitor, Pro-boroPro (PBP). Among them, 18 was revealed to be a DPP-IV-specific inhibitor, while the others also showed inhibitory activity toward another peptidase, aminopeptidase N (APN).