Title of article :
4-Arylcyclohexylalanine analogs as potent, selective, and orally active inhibitors of dipeptidyl peptidase IV
Author/Authors :
David E. Kaelin، نويسنده , , Abigail L. Smenton، نويسنده , , George J. Eiermann، نويسنده , , Huaibing He، نويسنده , , Barbara Leiting، نويسنده , , Kathryn A. Lyons، نويسنده , , Reshma A. Patel، نويسنده , , Sangita B. Patel، نويسنده , , Alexsandr Petrov، نويسنده , , Giovanna Scapin، نويسنده , , Joseph K. Wu، نويسنده , , Nancy A. Thornberry، نويسنده , , Ann E. Weber، نويسنده , , Joseph L. Duffy، نويسنده ,
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 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.
