2-[3-[2-[(2S)-2-Cyano-1-pyrrolidinyl]-2-oxoethylamino]-3-methyl-1-oxobutyl]-1,2,3,4-tetrahydroisoquinoline:A Potent,Selective,and Orally Bioavailable Dipeptide-Derived Inhibitor of Dipeptidyl Peptidase IV

摘要

Dipeptidyl peptidase IV (DPP-IV) inhibitors are expected to become a new type of antidiabetic drugs.Most known DPP-IV inhibitors often resemble the dipeptide cleavage products,with a proline mimic at the P1 site.As off-target inhibitions of DPP8 and/or DPP9 have shown profound toxicities in the in vivo studies,it is important to develop selective DPP-IV inhibitors for clinical usage.To achieve this,a new class of 2-[3-[[2-[(2S)-2-cyano-1-pyrrolidinyl]-2-oxoethyl]amino]-1-oxopropyl]-based DPP-IV inhibitors was synthesized.SAR studies resulted in a number of DPP-IV inhibitors,having IC_(50) values of <50 nM with excellent selectivity over both DPP8 (IC_(50) > 100 mu M) and DPP-II (IC_(50) > 30 mu M).Compound 21a suppressed the blood glucose elevation after an oral glucose challenge in Wistar rats and also inhibited plasma DPP-IV activity for up to 4 h in BALB/c mice.The results show that compound 21a possesses in vitro and in vivo activities comparable to those of NVP-LAF237 (4),which is in clinical development.