Synthesis and evaluation of [(1R)-1-amino-2-(2,5-difluorophenyl)ethyl]cyclohexanes and 4-[(1R)-1-amino-2-(2,5-difluorophenyl)ethyl]piperidines as DPP-4 inhibitors

A series of 4-amino cyclohexanes and 4-substituted piperidines were prepared and evaluated for inhibition of DPP-4. Analog 20q displayed both good DPP-4 potency and selectivity against other proteases, while derivative 20k displayed long half life and modest oral bioavailability in rat. The most potent analog, 3-(5-aminocarbonylpyridyl piperidine 53j, displayed excellent DPP-4 activity with good selectivity versus other proline enzymes.

Graphical abstractA novel series of 4-substituted-[(1R)-1-amino-2-(2,5-difluorophenyl)ethyl]cyclohexanes 1 and piperidines 2 were prepared and evaluated for inhibition of dipeptidyl dipeptidase IV (DPP-4) for treatment of type 2 diabetes.Figure optionsDownload full-size imageDownload as PowerPoint slide