(1,3‐Diphenyl‐1H‐Pyrazol‐4‐yl)‐Methylamine Analogues as Inhibitors of Dipeptidyl Peptidases

A number of pyrazole compounds reported in literatures elicit anti-hyperglycemic effects. By modifying the side chain of the heterocyclic skeleton, a new chemical class of DPP-IV inhibitors structurally derived from the (pyrazol-4-yl)-methylamine scaffold have been discovered and evaluated the biological activities of these inhibitors against DPP-IV, DPP8, DPP-II and FAP. The SAR studies showed the (1,3-diphenyl-1H-pyrazol-4-yl)-methylamines with 2,4-dichloro substituents at the 3-phenyl ring selectively preferred as DPP-IV inhibitors, whereas with difluoro substituents at the 3-phenyl ring selectively preferred as DPP8 inhibitors. The binding mode of representative compound 15h at the active site of DPP-IV was predicted by computer model. In additional, 15h exhibited the ability to significantly decrease the glucose excursion in mice.