4-Arylcyclohexylalanine analogs as potent, selective, and orally active inhibitors of dipeptidyl peptidase IV

A novel series of 4-arylcyclohexylalanine DPP-4 inhibitors was synthesized and tested for inhibitory activity as well as selectivity over the related proline-specific enzymes DPP-8 and DPP-9. Optimization of this series led to 28 (DPP-4 IC50 = 4.8 nM), which showed an excellent pharmacokinetic profile across several preclinical species. Evaluation of 28 in an oral glucose tolerance test demonstrated that this compound effectively reduced glucose excursion in lean mice.

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