Aminoacylpyrrolidine-2-nitriles: Potent and Stable Inhibitors of Dipeptidyl-Peptidase IV (CD 26)

Dipeptidyl-peptidase IV (EC 3.4.14.5) also known as CD26 is a membrane-bound serine peptidase which cleaves N-terminal dipeptides from a peptide chain containing a proline residue in the penultimate position. The enzyme is believed to play an important role in neuropeptide metabolism and T-cell activation. A series of aminoacylpyrrolidine-2-nitriles, in which the carboxyl group of proline is replaced by a nitrile group, was synthesized as inhibitors of dipeptidyl-peptidase IV. All compounds were found to competitively inhibit a homogeneous preparation of the rat kidney enzyme withK_ivalues in the low to submicromolar range. The nitriles presumably react with the active-site serine to form an imidate adduct. The compounds were stable following incubation either for 20 h at 37°C or 72 h at room temperature. They proved to be poor inhibitors of dipeptidyl-peptidase II and prolyl oligopeptidase. These studies demonstrate that the generally held concept that nitriles are poor inhibitors of serine proteinases needs to be reconsidered. Aminoacylpyrrolidine-2-nitriles by virtue of their ease of synthesis, stability, specificity, and inhibitory potency appear to be superior to other described dipeptidyl-peptidase IV inhibitors.