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

Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, NJ 07065, USA.
Bioorganic & Medicinal Chemistry Letters (Impact Factor: 2.33). 12/2007; 17(21):5806-11. DOI: 10.1016/j.bmcl.2007.08.049
Source: PubMed

ABSTRACT 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 IC(50)=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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