DPP-4 Inhibitory Activity Research Articles

Additive hypoglycaemic effect of nateglinide and exogenous glucagon-like peptide-1 in type 2 diabetes

We examined the postprandial glucose regulators nateglinide and GLP-1, separately and in combination, in people with type 2 diabetes. Nateglinide inhibited DPP-4 activity, reduced GLP-1 degradation and enhanced its insulinotropic and blood glucose lowering effect. Combining nateglinide and GLP-1 derivatives may effectively control postprandial glycaemia.

Hormonal and metabolic effects of morning or evening dosing of the dipeptidyl peptidase IV inhibitor vildagliptin in patients with type 2 diabetes

Vildagliptin is an orally active, potent inhibitor of dipeptidyl peptidase IV and was developed for the treatment of type 2 diabetes. In clinical trials, once or twice daily dosing with vildagliptin (up to 100 mg day(-1)) has been shown to reduce endogenous glucose production and fasting plasma glucose in patients with type 2 diabetes. The comparative efficacy of vildagliptin under a morning vs. evening dosing regimen has not previously been determined. Once daily dosing with vildagliptin 100 mg for 28 days improved glycaemic control in patients with type 2 diabetes independent of whether vildagliptin was administered in the morning or evening. Morning or evening dosing with vildagliptin had similar effects on 24 h glycaemic control and plasma concentrations of the hormones insulin, glucagon and glucagon-like peptide 1. This randomized, double-blind, crossover study compared post-prandial hormonal and metabolic effects of vildagliptin, (an oral, potent, selective inhibitor of dipeptidyl peptidase IV [DPP-4]) administered morning or evening in patients with type 2 diabetes. Forty-eight patients were randomized to once daily vildagliptin 100 mg administered before breakfast or before dinner for 28 days then crossed over to the other dosing regimen. Blood was sampled frequently after each dose at baseline (day -1) and on days 28 and 56 to assess pharmacodynamic parameters. Vildagliptin inhibited DPP-4 activity (>80% for 15.5 h post-dose), and increased active glucagon-like peptide-1 compared with placebo. Both regimens reduced total glucose exposure compared with placebo (area under the 0-24 h effect-time curve [AUE(0,24 h)]: morning -467 mg dl(-1) h, P= 0.014; evening -574 mg dl(-1) h, P= 0.003) with no difference between regimens (P= 0.430). Reductions in daytime glucose exposure (AUE(0,10.5 h)) were similar between regimens. Reduction in night-time exposure (AUE(10.5,24 h) was greater with evening than morning dosing (-336 vs.-218 mg dl(-1) h, P= 0.192). Only evening dosing significantly reduced fasting plasma glucose (-13 mg dl(-1), P= 0.032) compared with placebo. Insulin exposure was greater with evening dosing (evening 407 microU ml(-1) h; morning 354 microU ml(-1) h, P= 0.050). Both morning and evening dosing of once daily vildagliptin 100 mg significantly reduced post-prandial glucose in patients with type 2 diabetes; only evening dosing significantly decreased fasting plasma glucose. Although evening dosing with vildagliptin 100 mg tended to decrease night-time glucose exposure more than morning dosing, both regimens were equally effective in reducing 24 h mean glucose exposure (AUE(0,24 h)) in patients with type 2 diabetes.

ASP4000, a novel, selective, dipeptidyl peptidase 4 inhibitor with antihyperglycemic activity

ASP4000, (2 S)-1-{[(1 R,3 S,4 S,6 R)-6-hydroxy-2-azabicyclo[2.2.1]hept-3-yl]carbonyl}-2-pyrrolidinecar bonitrile hydrochloride, is a novel dipeptidyl peptidase (DPP) 4 inhibitor. In the present study, we characterized the compound as an oral antidiabetic agent both in vitro and in vivo. ASP4000 inhibited human recombinant DPP4 with an IC 50 value of 2.25 nM, and the enzyme–kinetic curve indicated that the inhibition type was competitive. In addition, ASP4000 also potently inhibited DPP4 activity in human, rat, dog, and monkey plasma at concentrations of the order of 10 − 9 M, and showed high selectivity against other related enzymes, including DPP8 and DPP9. The antihyperglycemic activity of ASP4000 in vivo was examined using Zucker fa/fa rats, a type 2 diabetes animal model. A single oral administration of ASP4000 at doses of 0.03–1 mg/kg suppressed plasma DPP4 activity, and then reduced the glucose level with increasing the active GLP-1 and insulin levels in oral glucose tolerance test. These results indicate that ASP4000 is a potent, competitive, selective DPP4 inhibitor with antihyperglycemic activity, and could be a promising candidate agent for the treatment of patients with type 2 diabetes.

(R)-8-(3-Amino-piperidin-1-yl)-7-but-2-ynyl-3-methyl-1-(4-methyl-quinazolin-2-ylmethyl)-3,7-dihydro-purine-2,6-dione (BI 1356), a Novel Xanthine-Based Dipeptidyl Peptidase 4 Inhibitor, Has a Superior Potency and Longer Duration of Action Compared with Other Dipeptidyl Peptidase-4 Inhibitors

BI 1356 [proposed trade name ONDERO; (R)-8-(3-amino-piperidin-1-yl)-7-but-2-ynyl-3-methyl-1-(4-methyl-quinazolin-2-ylmethyl)-3,7-dihydro-purine-2,6-dione] is a novel dipeptidyl peptidase (DPP)-4 inhibitor under clinical development for the treatment of type 2 diabetes. In this study, we investigated the potency, selectivity, mechanism, and duration of action of BI 1356 in vitro and in vivo and compared it with other DPP-4 inhibitors. BI 1356 inhibited DPP-4 activity in vitro with an IC(50) of approximately 1 nM, compared with sitagliptin (19 nM), alogliptin (24 nM), saxagliptin (50 nM), and vildagliptin (62 nM). BI 1356 was a competitive inhibitor, with a K(i) of 1 nM. The calculated k(off) rate for BI 1356 was 3.0 x 10(-5)/s (versus 2.1 x 10(-4)/s for vildagliptin). BI 1356 was >/=10,000-fold more selective for DPP-4 than DPP-8, DPP-9, amino-peptidases N and P, prolyloligopeptidase, trypsin, plasmin, and thrombin and was 90-fold more selective than for fibroblast activation protein in vitro. In HanWistar rats, the DPP-4 inhibition 24 h after administration of BI 1356 was more profound than with any of the other DPP-4 inhibitors. In C57BL/6J mice and Zucker fatty (fa/fa) rats, the duration of action on glucose tolerance decreased in the order BI 1356 > (sitagliptin/saxagliptin) > vildagliptin. These effects were mediated through control of glucagon-like peptide-1 and insulin. In conclusion, BI 1356 inhibited DPP-4 more effectively than vildagliptin, sitagliptin, saxagliptin, and alogliptin and has the potential to become the first truly once-a-day DPP-4 inhibitor for the treatment of type 2 diabetes.

Pharmacokinetics and pharmacodynamics of the DPP-4 inhibitor, LAF237, in patients with type 2 diabetes

Background LAF237 is a selective DPP-4 inhibitor under development as an anti-diabetic agents. The objective of this study was to assess the PK/PD in patients with type 2 diabetes (T2D). Methods Thirteen patients were enrolled and 12 completed this study. Each patient was randomly assigned to receive one of the four treatments for 28 days: placebo (PBO), 10, 25, or 100 mg of LAF237 bid. Blood samples were collected on day 28 for measurement of LAF237, DPP-4, GLP-1, glucose and insulin over 16 hr while standard mixed meals were served. Results LAF237 was rapidly absorbed and the Cmax was observed during 1~2 hr. Both Cmax and AUC increased dose proportionally. More than 90% DPP-4 inhibition was achieved after all doses, while the duration of >90% DPP-4 inhibition increased with dose. LAF237 100 mg bid increased GLP-1 levels >2 fold compared to placebo. Mean glucose levels over 14 hr were significantly reduced by 10% and 19%, respectively, at 25 mg and 100 mg bid compared to PBO (p<0.05). LAF237 at 10 mg bid did not show effect on glucose. Since insulin levels were maintained while glycemic levels were reduced, the results suggest that insulin secretion was increased relative to the observed glucose levels. Conclusions LAF237 was well tolerated at dose up to 100 mg bid in patients with T2D. LAF237 was rapidly absorbed and significantly inhibited DPP-4 activity. Glucose levels were significantly reduced after 25 and 100 mg bid dosing, indicating that LAF237 is a promising new approach for the treatment of patients with T2D. Clinical Pharmacology & Therapeutics (2005) 77, P56–P56; doi: 10.1016/j.clpt.2004.12.104