DIPEPTIDE PHOSPHONATES AS INHIBITORS OF DIPEPTIDYL PEPTIDASE-IV

A series of dipeptides which contained phosphonate analogs of proline and piperidine-2-carboxylic acid (homoproline) have been synthesized and tested as inhibitors of DPP-IV. The rates of inhibition of DPP-IV by these compounds are moderate, but the inhibitors are quite specific. The best inhibitor in the series is Ala-Pip(P)(OPh-4-Cl)(2) (13), which has a k(inact) of 0.353 s(-1) and K-I of 236 mu M. The DPP-IV inhibitors Ala-Pro(P)(OPh)(2) (6), Ala-Pro(P)(OPh-4-Cl)(2) (12), and Ala-Pip(P)(OPh-4-Cl)(2) (13) do not inhibit trypsin, human leukocyte elastase (HLE), porcine pancreatic elastase (PPE), adetylcholinesterase, papain, and cathepsin B. However, compounds 12 and 13 inhibited chymotrypsin slowly. Most of these dipeptides containing a homoproline phosphonate residue (Pip(P)) or a Pro phosphonate residue (pro(P)) at the P-1 site are stable in a pH 7.8 buffer with half-lives of several hours to several days. DPP-IV inhibited by 6, 7 (Ala-Pip(P)(OPh)(2)), 12, or 13 is quite stable, and no enzyme activity was recovered after removal of excess inhibitor and incubation buffer for 1 day. Since the phosphonate inhibitors are specific toward DPP-IV and the inhibited enzymes are stable, they should be useful in establishing the biological functions of DPP-IV and may be useful therapeutically in the prevention of the rejection of transplanted tissue.