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-PipP(OPh-4-Cl)2 (13), which has a k(inact) of 0.353 s-1 and KI of 236 microM. The DPP-IV inhibitors Ala-ProP(OPh)2 (6), Ala-ProP(OPh-4-Cl)2 (12), and Ala-PipP(OPh-4-Cl)2 (13) do not inhibit trypsin, human leukocyte elastase (HLE), porcine pancreatic elastase (PPE), acetylcholinesterase, papain, and cathepsin B. However, compounds 12 and 13 inhibited chymotrypsin slowly. Most of these dipeptides containing a homoproline phosphonate residue (PipP) or a Pro phosphonate residue (ProP) at the P1 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-PipP(OPh)2), 12, or 13 is quite stable, and no enzyme activity was recovered after removal of excess inhibitor and incubation in 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.
Boduszek
B
B
School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta 30332-0400.
Oleksyszyn
J
J
Kam
C M
CM
Selzler
J
J
Smith
R E
RE
Powers
J C
JC
D002021:Buffers; D004151:Dipeptides / Q000494:pharmacology*; D018819:Dipeptidyl Peptidase 4 / Q000187:drug effects*; D005260:Female; D006207:Half-Life; D006801:Humans; D006868:Hydrolysis; D007700:Kinetics; D063065:Organophosphonates / Q000494:pharmacology*; D010920:Placenta / Q000201:enzymology; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology*
D002021:Buffers; D004151:Dipeptides; D063065:Organophosphonates; D015842:Serine Proteinase Inhibitors; D018819:Dipeptidyl Peptidase 4