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 with Ki values 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 degrees 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. Amino-acylpyrrolidine-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.
D000818:Animals; D001665:Binding Sites; D001667:Binding, Competitive; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000378:metabolism; D004794:Enzyme Repression; D007668:Kidney / Q000201:enzymology; D009570:Nitriles / Q000138:chemical synthesis* / Q000378:metabolism; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000378:metabolism; D051381:Rats; D012694:Serine / Q000378:metabolism
D004791:Enzyme Inhibitors; D009570:Nitriles; D011759:Pyrrolidines; D012694:Serine; D018819:Dipeptidyl Peptidase 4; C032519:pyrrolidine