Inhibition of dipeptidyl peptidase IV by fluoroolefin-containing N -peptidyl- O -hydroxylamine peptidomimetics

Inhibition of dipeptidyl peptidase IV by fluoroolefin-containing N-peptidyl-O-hydroxylamine peptidomimetics

Department of Chemistry, University at Albany, Albany, NY 12222

Communicated by George A. Olah, University of Southern California, Los Angeles, CA (received for review April 8, 1998)

Abstract

Dipeptidyl peptidase IV (EC 3.4.14.5; DPP IV), also known as the leukocyte differentiation antigen CD26 when found as an extracellular membrane-bound proline specific serine protease, cleaves a dipeptide from the N terminus of a polypeptide chain containing a proline residue in the penultimate position. Here we report that known (Z)-Ala-ψ[CF=C]-Pro dipeptide isosteres 1 and 2, which contain O-acylhydroxylamines, were isolated as diastereomeric pairs u-1, l-1, and l-2. The effect of each 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 containing N-peptidyl-O-hydroxylamine peptidomimetics, by virtue of their inhibitory potency and stability, are superior to N-peptidyl-O-hydroxylamine inhibitors derived from an Ala-Pro dipeptide.

Footnotes

↵ * To whom reprint requests should be addressed at: Department of Chemistry, University at Albany, 1400 Washington Avenue, Albany, NY 12222. e-mail: JTW06{at}cnsvax.albany.edu.
Data deposition: The atomic coordinates and structure factors have been deposited in the Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge, CB2 1EZ, United Kingdom (reference 103375).
ABBREVIATION:

DPP IV,

dipeptidyl peptidase IV