A series of dipeptides which contained phosphonate analogs of proline
and piperidine-2-carboxylic acid (homoproline) have been synthesized a
nd tested as inhibitors of DPP-IV. The rates of inhibition of DPP-IV b
y 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), whi
ch has a k(inact) of 0.353 s(-1) and K-I of 236 mu M. The DPP-IV inhib
itors Ala-Pro(P)(OPh)(2) (6), Ala-Pro(P)(OPh-4-Cl)(2) (12), and Ala-Pi
p(P)(OPh-4-Cl)(2) (13) do not inhibit trypsin, human leukocyte elastas
e (HLE), porcine pancreatic elastase (PPE), adetylcholinesterase, papa
in, and cathepsin B. However, compounds 12 and 13 inhibited chymotryps
in slowly. Most of these dipeptides containing a homoproline phosphona
te residue (Pip(P)) or a Pro phosphonate residue (pro(P)) at the P-1 s
ite 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 o
f excess inhibitor and incubation buffer for 1 day. Since the phosphon
ate inhibitors are specific toward DPP-IV and the inhibited enzymes ar
e stable, they should be useful in establishing the biological functio
ns of DPP-IV and may be useful therapeutically in the prevention of th
e rejection of transplanted tissue.