INHIBITION OF DIPEPTIDYL PEPTIDASE-IV BY FLUOROOLEFIN-CONTAINING N-PEPTIDYL-O-HYDROXYLAMINE PEPTIDOMIMETICS

Dipeptidyl peptidase IV (EC 3.4.14.5; DPP IV), also known as the leuko cyte differentiation antigen CD26 when found as an extracellular membr ane-bound proline specific serine protease, cleaves a dipeptide from t he N terminus of a polypeptide chain containing a proline residue in t he penultimate position. Here we report that known (Z)-Ala-psi[CF=C]-P ro dipeptide isosteres 1 and 2, which contain O-acylhydroxylamines, we re isolated as diastereomeric pairs u-1, l-1, and l-2. The effect of e ach diastereomeric pair as an inhibitor of human placental dipeptidyl peptidase DPP IV has been examined. The inhibition of DPP IV by these compounds is rapid and efficient. The diastereomeric pair u-1 exhibits very potent inhibitory activity with a K-i of 188 nM. Fluoroolefin co ntaining N-peptidyl-O-hydroxylamine peptidomimetics, by virtue of thei r inhibitory potency and stability, are superior to N-peptidyl-O-hydro xylamine inhibitors derived from an Ala-Pro dipeptide.