J. Med.Chem. 1994, 37, 3969-3976.pdf (original) (raw)

Dipeptide Phosphonates as Inhibitors of Dipeptidyl Peptidase IV

Journal of Medicinal Chemistry, 1994

A series of dipeptides which contained phosphonate analogs of proline and piperidine-2carboxylic 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 (131, which has a Kinact of 0.353 s-l and KI of 236 pM. 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 PI 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 buf'fer 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.

An aminomethylpyrimidine DPP-IV inhibitor with improved properties

Bioorganic & Medicinal Chemistry Letters, 2004

A recently identified DPP-IV inhibitor (1) was found to induce phospholipidosis and to inhibit CYP3A4. A small series of less lipophilic and less amphiphilic analogues was synthesized in an effort to overcome these issues. One compound from this series was equipotent to 1, did not induce phospholipidosis and showed a reduced CYP3A4 inhibition.

Enantioselective and Reversible Inhibition of Trypsin and .alpha.-Chymotrypsin by Phosphonate Esters

Biochemistry, 1994

Trypsin is inactivated by the levorotatory enantiomers (most likely Ps) of 4-nitrophenyl 4-H-, 4-CH3-, 4-OCH3-, and 4-C1-phenacyl methylphosphonates (PMNs) with second-order rate constants between 23 1 and 884 M-l s-l. 4-NO2-PMN hydrolyzes before inhibiting the enzyme. The second-order rate constants for the inactivation of a-chymotrypsin by the levorotatory enantiomers of the five PMNs are between 37 000 and 770 000 M-l s-l, and those for the dextrorotatory enantiomers are between 400 and 640 M-l s-l; the enantioselectivity is 90-1 880. Specific rotation [(rl2*~ of the faster-reacting enantiomer of 4-CH3-PMN with trypsin and a-chymotrypsin is -30 f 6'. 31P N M R of the adducts shows a signal at 41.0 ppm, 10

Dipeptide-derived diphenyl phosphonate esters: mechanism-based inhibitors of dipeptidyl peptidase IV

Biochimica et Biophysica Acta (BBA) - General Subjects, 1996

A number of dipeptide diphenyl phosphonate esters were studied as inhibitors of dipeptidyl peptidase IV, focusing on the role of the P2 residue in the inactivation process. The active compounds were slow irreversible inhibitors of the catalytic activity of the enzyme. With proline (or alanine) in the PI position, the rate constants of inactivation correlated with the acylation rate constants reported fbr homologous dipeptide derived substrates. The kinetic data indicate that the mechanism of inhibition consists of the formation of a fairly weak initial complex, followed by a slow irreversible inactivation step. This indicates that, as in the case of trypsin-like proteinases, dipeptide diphenyl phosphonate esters form a covalent adduct with the catalytic site of DPP IV, even though this enzyme belongs to a completely distinct class of serine peptidases. Enantioselectivity and secondary specificity further support the evidence that diphenyl phosphonate esters are mechanism-based inhibitors. The dipeptide diphenyl phosphonate esters had a half-life of 3-10 h at 37°C in Tris buffer. The inhibitors were degraded in human plasma, depending on the type of amino-terminal amino acid. The compound with proline in the P2 position was the most resistant to degradation in plasma. Due to their stability and the irreversible nature of the inhibition, the diphenyl phosphonate esters promise to be useful tools in the continuing investigation of the physiological function of dipeptidyl peptidase IV.

J. Med.Chem. 1994, 37, 226-231.pdf

A series of new peptidyl (a-aminoalky1)phosphonate diphenyl esters containing the 4-amidinophenyl group were synthesized and tested as irreversible inhibitors for thrombin and other trypsin-like enzymes. These phosphonates irreversibly inhibited several coagulation enzymes and trypsin.

Biochemistry, pharmacokinetics, and toxicology of a potent and selective DPP8/9 inhibitor

Biochemical Pharmacology, 2009

DPP-IV (EC 3.4.14.5) is a validated drug target for human type II diabetes. DPP-IV inhibitors without DPP8/9 inhibitory activity have been sought because a possible association has been reported between a ''DPP8/9 inhibitor'' and severe toxicity in animals. However, at present, it is not known whether the observed toxicity is associated with DPP8/9 inhibition, or an off-target effect induced by the compound. We investigated whether the inhibition of DPP8/9 is the cause of the severe toxicity in animals using a very potent and selective DPP8/9 inhibitor with different pharmacophore, 1G244. By Ki measurement, 1G244 is 15-and 8-fold more potent against DPP8 and DPP9, respectively, than the ''DPP8/9 inhibitor''. Strikingly, the ''DPP8/9 inhibitor'' does not penetrate the plasma membrane but remains outside the cells, whereas 1G244 readily enters the cells, even at low doses. By repeatedly exposing Sprague-Dawley rats to 1G244 by intravenous injection for a period of 14 days, we observed no significant toxicological symptoms associated with 1G244. Blood and serum chemistry parameters were all within the normal ranges for the treated animals. Because of the high potency, good membrane penetration and adequate tissue distribution of 1G244, the mild symptoms observed are probably associated with DPP8/9 inhibition.