Pyrrolidides: Synthesis and structure-activity relationship as inhibitors of dipeptidyl peptidase IV

Abstract

Dipeptidyl peptidase IV cleaves specifically the peptide bond at the carboxyl side of a proline at the penultimate N-terminal position of a peptide. It is thought to be important for the regulation of biologically active peptides. Moreover, it has been identified as an activation marker of T-lymphocytes (CD26). Pyrrolidides and thiazolidides are known as reversible inhibitors of DPP IV. Several homologues, unsaturated, open and 3-substituted analogues were synthesized in order to determine the structure activity relationship of the P-1 site. L-Isoleucine was taken as P-2 amino acid. 1-(L-Isoleucyl)-3(S)-fluoropyrrolidine is about as active as the non-fluorinated compound and behaves as a competitive inhibitor. Other changes decrease or abolish the activity.