Potent Dipeptidyl Peptidase-4 Inhibitor Research Articles

Discovery and Rational Design of Natural-Product-Derived 2-Phenyl-3,4-dihydro-2H-benzo[f]chromen-3-amine Analogs as Novel and Potent Dipeptidyl Peptidase 4 (DPP-4) Inhibitors for the Treatment of Type 2 Diabetes.

Starting from the lead isodaphnetin, a natural product inhibitor of DPP-4 discovered through a target fishing docking based approach, a series of novel 2-phenyl-3,4-dihydro-2H-benzo[f]chromen-3-amine derivatives as potent DPP-4 inhibitors are rationally designed utilizing highly efficient 3D molecular similarity based scaffold hopping as well as electrostatic complementary methods. Those ingenious drug design strategies bring us approximate 7400-fold boost in potency. Compounds 22a and 24a are the most potent ones (IC50 ≈ 2.0 nM) with good pharmacokinetic profiles. Compound 22a demonstrated stable pharmacological effect. A 3 mg/kg oral dose provided >80% inhibition of DPP-4 activity within 24 h, which is comparable to the performance of the long-acting control omarigliptin. Moreover, the efficacy of 22a in improving the glucose tolerance is also comparable with omarigliptin. In this study, not only promising DPP-4 inhibitors as long acting antidiabetic that are clinically on demand are identified, but the target fish docking and medicinal chemistry strategies were successfully implemented.

A concise review of the bioanalytical methods for the quantitation of sitagliptin, an important dipeptidyl peptidase-4 (DPP4) inhibitor, utilized for the characterization of the drug.

Inhibition of dipeptidyl peptidase-4 (DPP4) is an emerging therapeutic approach for treating type 2 diabetes and has revolutionized the concept of diabetes management. Sitagliptin is the first approved orally active, potent, selective and nonpeptidomimetic DPP4 inhibitor. Incidence of hypoglycemia and weight gain is negligible with sitagliptin treatment. It is used as monotherapy or in combination with other anti-diabetic drugs to treat type 2 diabetes. There are numerous bioanalytical methods published for the analysis of sitagliptin in preclinical and clinical samples. This review focuses on the various HPLC and LC-MS/MS methods that have been used to analyze sitagliptin in various biological matrices. A small section is devoted to the bioanalysis of other DPP4 inhibitors such as vildagliptin, saxagliptin and linagliptin. This review provides key information in a concise manner regarding sample processing options, chromatographic/detection conditions and validation parameters of the chosen methods for sitagliptin and other DPP4 inhibitors.

Design, Synthesis, and Pharmacological Evaluation of Fused β-Homophenylalanine Derivatives as Potent DPP-4 Inhibitors.

Dipeptidyl peptidase-4 (DPP-4) inhibitors are accepted as a favorable class of agents for the treatment of type 2 diabetes. Herein, a series of fused β-homophenylalanine derivatives as novel DPP-4 inhibitors were designed, synthesized, and evaluated for their inhibitory activities against DPP-4. Most of them displayed excellent DPP-4 inhibitory activities and good selectivity. Among them, 9aa, 18a, and 18m also showed good efficacy in an oral glucose tolerance test (OGTT) in ICR mice. Moreover, when dosed 8 h prior to glucose challenge, 18m showed significantly greater potency than sitagliptin. It thus provides potential candidates for the further development into potent drugs targeting DPP-4.

Synthesis and Evaluation of Novel Xanthone Derivatives as Potent Dipeptidyl Peptidase-4 Inhibitors

Synthesis and Evaluation of Novel Xanthone Derivatives as Potent Dipeptidyl Peptidase-4 Inhibitors

(R)-3-Amino-1-((3aS,7aS)-octahydro-1H-indol-1-yl)-4-(2,4,5-trifluorophenyl)butan-1-one derivatives as potent inhibitors of dipeptidyl peptidase-4: Design, synthesis, biological evaluation, and molecular modeling

A series of (R)-3-amino-1-((3aS,7aS)-octahydro-1H-indol-1-yl)-4-(2,4,5-trifluorophenyl)butan-1-one derivatives was designed, synthesized, and evaluated as novel inhibitors of dipeptidyl peptidase-4 (DPP-4) for the treatment of type 2 diabetes. Most of the synthesized compounds demonstrated good inhibition activities against DPP-4. Among these, compounds 3e, 4c, 4l, and 4n exhibited prominent inhibition activities against DPP-4, with IC50s of 0.07, 0.07, 0.14, and 0.17μM, respectively. The possible binding modes of compounds 3e and 4n with dipeptidyl peptidase-4 were also explored by molecular docking simulation. These potent DPP-4 inhibitors were optimized for the absorption, distribution, metabolism, and excretion (ADME) properties, and compound 4n displayed an attractive pharmacokinetic profile (F=96.3%, t1/2=10.5h).

Efficacy and Safety of Vildagliptin as Add-on to Metformin in Japanese Patients with Type 2 Diabetes Mellitus

IntroductionThe objective of this study was to evaluate the efficacy and safety of vildagliptin, a potent dipeptidyl peptidase-4 inhibitor, as an add-on to metformin in Japanese patients with type 2 diabetes mellitus (T2DM).MethodsThis multicenter, 12-week, randomized, double-blind, placebo-controlled, parallel-arm study compared vildagliptin 50 mg bid with placebo in T2DM patients who were inadequately controlled [glycosylated hemoglobin (HbA1c) 7.0–10.0%] on a stable daily dose of metformin monotherapy (250 mg bid or 500 mg bid).ResultsA total of 139 patients were randomized to receive either vildagliptin (n = 69) or placebo (n = 70). Patient demographics were comparable between the groups at baseline. After 12 weeks of treatment, adjusted mean change in HbA1c was −1.1% in the vildagliptin group (baseline 8.0%) and −0.1% in the placebo group (baseline 8.0%), with a between-treatment difference of −1.0% (P < 0.001). Vildagliptin showed a similar reduction in HbA1c of −1.1% for both the subpopulations of patients receiving metformin 250 mg bid or 500 mg bid (P < 0.001 vs. baseline). Significantly more patients in the vildagliptin group achieved an HbA1c target of ≤6.5% (30.9%) and <7.0% (64.1%) compared with the placebo group (P < 0.001). The between-treatment difference in adjusted mean change in fasting plasma glucose was −1.6 mmol/L (P < 0.001) in favor of vildagliptin. Patients in the vildagliptin and placebo groups reported comparable incidences of adverse events (44.1% vs. 41.4%). No deaths or hypoglycemic events were reported in the study.ConclusionsVildagliptin 50 mg bid added to metformin improved glycemic control without any tolerability issues and hypoglycemia in Japanese patients with T2DM inadequately controlled on metformin monotherapy.Electronic supplementary materialThe online version of this article (doi:10.1007/s13300-014-0059-x) contains supplementary material, which is available to authorized users.

Efficacy and safety of nateglinide plus vildagliptin combination therapy compared with switching to vildagliptin in type 2 diabetes patients inadequately controlled with nateglinide.

To investigate the efficacy and safety of vildagliptin, a potent dipeptidyl peptidase-4 inhibitor, as add-on to nateglinide, compared with switching to vildagliptin in Japanese type2 diabetes patients poorly controlled with nateglinide. A total of 40 patients inadequately controlled with nateglinide were randomized to the switching group (n=20, switching from nateglinide to vildagliptin) or combination group (n=20, nateglinide plus vildagliptin). A meal tolerance test was carried out at weeks 0 and 24. The mean changes in glycated hemoglobin from baseline to week 24 were -1.2±0.3% and -0.3±0.5% in patients of the combination and switching groups, respectively, and the difference between the groups was statistically significant (P<0.001). The mean changes in area under the curve of glucose from 0 to 180min (AUC0-180min) from baseline to week 24 was -361±271.3mmol·min/L in patients of the combination group compared with 141±241.9mmol·min/L in those of the switching group (P<0.001). The incidence of hypoglycemic events was low (three in the combination group), and none of the patients developed severe hypoglycemia. Although the addition of vildagliptin to nateglinide did not significantly increase insulin secretion relative to glucose elevation (ISG) after meal load (ISG0-180min: AUC0-180min insulin/AUC0-180min glucose) in comparison with that in baseline, the mean ISG0-30min 24weeks after addition of vildagliptin to nateglinide was significantly higher than that at baseline. In contrast, switching from nateglinide to vildagliptin reduced the mean ISG0-180min, relative to baseline. The combination therapy of vildagliptin and nateglinide is effective and safe in Japanese type2 diabetes, and the improved glycemic control is as a result of augmentation of nateglinide-induced early phase insulin secretion. This trial was registered with UMIN (no. ID000004010).

Synthesis and biological evaluation of novel benzyl-substituted (S)-phenylalanine derivatives as potent dipeptidyl peptidase 4 inhibitors

A series of novel benzyl-substituted (S)-phenylalanine derivatives were synthesized and evaluated for their dipeptidyl peptidase 4 (DPP-4) inhibitory activity and selectivity. It was found that most synthesized target compounds were potent DPP-4 inhibitors with IC50 values in 3.79–25.52nM, which were significantly superior to that of the marketed drug sitagliptin. Furthermore, the 4-fluorobenzyl substituted phenylalanine derivative 6g not only displayed the potent DPP-4 inhibition with an IC50 value of 3.79nM, but also showed better selectivity against DPP-4 over other related enzymes including DPP-7, DPP-8, and DPP-9. In an oral glucose tolerance test (OGTT) in normal Sprague Dawley rats, compound 6g reduced blood glucose excursion in a dose-dependent manner.

Vildagliptin in the Treatment of Type 2 Diabetes Mellitus

Abstract Novel therapeutic approaches are continuously being researched in type 2 diabetes. The incretin class of anti-diabetic agents, consisting of glucagon-like peptide-1 agonists and dipeptidyl peptidase-4 inhibitors, has already found an important place in the current guidelines. Vildagliptin is a potent dipeptidyl peptidase-4 inhibitor, with numerous trials in type 2 diabetes treatment, both in monotherapy and in combination therapy. This review focuses on vildagliptin pharmacological properties, clinical efficacy and safety, and pharmacoeconomic data.

Profile of vildagliptin in type 2 diabetes: efficacy, safety, and patient acceptability

Vildagliptin is a selective and potent dipeptidyl peptidase-4 inhibitor that improves glycemic control by inhibiting the degradation of both endogenous glucagon-like peptide-1 and glucose-dependent insulinotropic peptide. This article is a comprehensive review of the safety and efficacy of vildagliptin in patients with type 2 diabetes. Clinical evidence has proven that it effectively decreases hemoglobin A1c with a low risk of hypoglycemia and is weight neutral. The addition of vildagliptin to metformin improves glucose control and significantly reduces gastrointestinal adverse events, particularly in patients inadequately controlled with metformin monotherapy. Its long-term advantages include preservation of β-cell function, reduction in total cholesterol, decrease in fasting lipolysis in adipose tissue, and triglyceride storage in non-fat tissues. Vildagliptin is well tolerated with a low incidence of AEs, and it does not increase the risk of cardiovascular/cerebrovascular (CCV) events. It can be taken before or after meals, and has little drug interaction, thus it will be well accepted.

A novel, potent, and long-lasting dipeptidyl peptidase-4 inhibitor, teneligliptin, improves postprandial hyperglycemia and dyslipidemia after single and repeated administrations

Dipeptidyl peptidase-4 (DPP-4) inhibitors have been demonstrated to improve glycemic control, in particular postprandial hyperglycemic control, in patients with type 2 diabetes. Teneligliptin is a novel chemotype prolylthiazolidine-based DPP-4 inhibitor. The present study aimed to characterize the pharmacological profiles of teneligliptin in vitro and in vivo. Teneligliptin competitively inhibited human plasma, rat plasma, and human recombinant DPP-4 in vitro, with IC50 values of approximately 1nmol/l. Oral administration of teneligliptin in Wistar rats resulted in the inhibition of plasma DPP-4 with an ED50 of 0.41mg/kg. Plasma DPP-4 inhibition was sustained even at 24h after administration of teneligliptin. An oral carbohydrate-loading test in Zucker fatty rats showed that teneligliptin at ≥0.1mg/kg increased the maximum increase in plasma glucagon-like peptide-1 and insulin levels, and reduced glucose excursions. This effect was observed over 12h after a dose of 1mg/kg. An oral fat-loading test in Zucker fatty rats also showed that teneligliptin at 1mg/kg reduced triglyceride and free fatty acid excursions. In Zucker fatty rats, repeated administration of teneligliptin for two weeks reduced glucose excursions in the oral carbohydrate-loading test and decreased the plasma levels of triglycerides and free fatty acids under non-fasting conditions. The present studies indicate that teneligliptin is a potent, competitive, and long-lasting DPP-4 inhibitor that improves postprandial hyperglycemia and dyslipidemia by both single and repeated administrations.

Recent Advances in Non-Peptidomimetic Dipeptidyl Peptidase 4 Inhibitors: Medicinal Chemistry and Preclinical Aspects

Dipeptidyl peptidase 4 (DPP-4), a substrate-specific serine protease, has been validated as a promising drug target for the treatment of type 2 diabetes. DPP-4 inhibitors significantly lowered blood glucose levels in patients with type 2 diabetes without common body weight gain, hypoglycemia and gastrointestinal disturbance side effects. Therefore, DPP-4 inhibitors attracted more and more attention. In particular, non-peptidomimetic DPP-4 inhibitors have been a focus of research and development and made great progress in recent years, which resulted in the discovery of a wide variety of potent non-peptidomimetic DPP-4 inhibitors. Some of them, such as sitagliptin, alogliptin and linagliptin have already been used as marketed drugs, while others have been into clinical trials. Based on the core structural features of non-peptidomimetic DPP-4 inhibitors, seven types were classified in the article. For each type, we focused on the description of strategies for design and optimization, together with a discussion on concluded structure-activity relationships (SAR). In addition, the contribution of specific substituents to the inhibition of DPP-4 was summarized. Selectivity towards the inhibition of DPP-4 over dipeptidyl peptidase 8 (DPP-8) and dipeptidyl peptidase 9 (DPP-9) was also presented.

Vildagliptin selectively ameliorates GLP-1, GLUT4, SREBP-1c mRNA levels and stimulates β-Cell proliferation resulting in improved glucose homeostasis in rats with streptozotocin-induced diabetes

ObjectiveInhibitors of dipeptidyl peptidase-4 (DPP-4), a key regulator of the actions of incretin hormones, exert antihyperglycemic effects in type 2 diabetic patients. A major unanswered question concerns the potential ability of DPP-4 inhibition to have beneficial disease-modifying effects, specifically to attenuate loss of pancreatic β-cell mass and function due to oxidative stress induced inflammation. Here, we investigated the effects of a potent and selective DPP-4 inhibitor vildagliptin on glycemic control, pancreatic β-cell mass and function, genes and proteins expressions, tumor necrosis factor-alpha, and nitric oxide in an n2-STZ diabetic model of rat with defects in insulin sensitivity and secretion. MethodTo induce NIDDM, STZ (sigma chemicals, USA) (90 mg/kg) was administered i.p. to a group of 2 days old pups. Another group of pups received only saline. The pups were weaned for 21 days, and 6 weeks after the injection of STZ, the animals were checked for fasting glucose level (FPG) ≥160 mg/dl were considered as diabetic. ResultsSignificant and dose-dependent correction of postprandial and fasting hyperglycemia was observed in diabetic rats following 8 weeks of chronic therapy. Treatment with vildagliptin showed increase in the number of insulin-positive β-cells in islets and improved the expressions of genes and proteins are responsible for insulin secretions. In addition, treatment of rats with vildagliptin significantly increased insulin content; and decreased the nitric oxide and TNF-alpha concentration. ConclusionThese findings suggest that DPP-4 inhibitors may offer long-lasting efficacy in the treatment of diabetes mellitus by modifying the courses of the disease.

Characterization of the In Vitro and In Vivo Metabolism and Disposition and Cytochrome P450 Inhibition/Induction Profile of Saxagliptin in Human

Saxagliptin is a potent dipeptidyl peptidase-4 inhibitor approved for the treatment of type 2 diabetes mellitus. The pharmacokinetics and disposition of [(14)C]saxagliptin were investigated in healthy male subjects after a single 50-mg (91.5 μCi) oral dose. Saxagliptin was rapidly absorbed (T(max), 0.5 h). Unchanged saxagliptin and 5-hydroxy saxagliptin (M2), a major, active metabolite, were the prominent drug-related components in the plasma, together accounting for most of the circulating radioactivity. Approximately 97% of the administered radioactivity was recovered in the excreta within 7 days postdose, of which 74.9% was eliminated in the urine and 22.1% was excreted in the feces. The parent compound and M2 represented 24.0 and 44.1%, respectively, of the radioactivity recovered in the urine and feces combined. Taken together, the excretion data suggest that saxagliptin was well absorbed and was subsequently cleared by both urinary excretion and metabolism; the formation of M2 was the major metabolic pathway. Additional minor metabolic pathways included hydroxylation at other positions and glucuronide or sulfate conjugation. Cytochrome P450 (P450) enzymes CYP3A4 and CYP3A5 metabolized saxagliptin and formed M2. Kinetic experiments indicated that the catalytic efficiency (V(max)/K(m)) for CYP3A4 was approximately 4-fold higher than that for CYP3A5. Therefore, it is unlikely that variability in expression levels of CYP3A5 due to genetic polymorphism will impact clearance of saxagliptin. Saxagliptin and M2 each showed little potential to inhibit or induce important P450 enzymes, suggesting that saxagliptin is unlikely to affect the metabolic clearance of coadministered drugs that are substrates for these enzymes.

Pharmacokinetics and Pharmacodynamics of KR-66223 a Novel DPP-4 Inhibitor

KR-66223 is a novel dipeptidyl peptidase-4 (DPP-4) inhibitor that is under development for the treatment of type 2 diabetes. We studied the pharmacokinetic and pharmacodynamic characteristics of KR-66223 in rats, monkeys, and dogs to predict PK/PD profiles in humans. KR-66223 exhibited a moderate volume of distribution (0.3-1.8 L/kg), moderate systemic clearance (1-1.76 L/h/kg), long half-life (>3 h), and low oral bioavailability (below 2.5% in all tested species). The EC(50)s for DPP-4 inhibition as calculated by the E(max) model was below 4.25 ng/mL across all species, confirming KR-66223 as a potent DPP-4 inhibitor. In vitro plasma protein binding suggested that it was available (69-89%), correlating with its volume of distribution in animals. Using allometric scaling and the E(max) model, human systemic clearance, volume of the central compartment, volume of the peripheral compartment, and EC₅₀ for DPP-4 inhibition were predicted to be 0.31 L/h/kg, 0.1 L/kg, 2.4 L/kg, and 3 ng/mL, respectively. These results can serve as a valuable foundation for future clinical trials.

Chronic Treatment with the Dipeptidyl Peptidase-4 Inhibitor BI 1356 [(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] Increases Basal Glucagon-Like Peptide-1 and Improves Glycemic Control in Diabetic Rodent Models

Antidiabetic effects of dipeptidyl peptidase-4 (DPP-4) inhibitors are exerted by potentiation of the biological activity of incretin hormones like glucagon-like peptide (GLP)-1. 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 competitive, selective, potent, and long-acting DPP-4 inhibitor under clinical development for the treatment of type 2 diabetes. The effect of 1 to 2 months of chronic dosing of BI 1356 in two different animal models was investigated. The first is a primarily genetic model (Zucker diabetic fatty rats), and the second is a nongenetic model (mice with diabetes induced by a combination of high-fat diet and low-dose streptozotocin). BI 1356 was shown to lower HbA1c after multiple dosing in both models. The improvement of glycemic control achieved in disease models of different etiology suggests that BI 1356 would also be efficacious in treating a broad spectrum of type 2 diabetic patients. In addition, multiple dosing of BI 1356 leads to a sustained increase in basal levels of active GLP-1 in the systemic circulation, with expected long-term benefits on pancreatic alpha- and beta-cells. The effects on HbA1c and GLP-1 were superior to the short-acting DPP-4 inhibitor vildagliptin, demonstrating the potential of BI 1356 as a once daily treatment for type 2 diabetes at low therapeutic doses.

Dipeptidyl peptidase 4 inhibition and vildagliptin therapy for type 2 diabetes

Dipeptidyl peptidase 4 (DPP-4) inhibition prevents the rapid degradation of the incretins, glucagon-like peptide 1 and glucose-dependent insulinotropic peptide. Incretins have beneficial effects on glycaemic control in patients with type 2 diabetes through their effects on both alpha- and beta-cells in the pancreas and possibly through additional non-pancreatic effects. Vildagliptin is a potent and selective oral DPP-4 inhibitor that has been studied both as monotherapy and in combination with other antidiabetic treatments. This agent has been shown to be well tolerated and is efficacious in reducing glycosylated haemoglobin, fasting plasma glucose and postprandial glucose levels in trials lasting up to 52 weeks. Vildagliptin is weight neutral, does not cause oedema and is associated with a very low incidence of hypoglycaemia. Recently reported clinical data have helped to further clarify the mechanisms of action and effects of vildagliptin. These results suggest that vildagliptin, as a member of the novel class of DPP-4 inhibitors, has the potential to significantly change the clinical management of diabetes. Future research will further define its use in various patient populations and its possible disease-modifying effects.

Chronic Inhibition of Dipeptidyl Peptidase-4 With a Sitagliptin Analog Preserves Pancreatic β-Cell Mass and Function in a Rodent Model of Type 2 Diabetes

Inhibitors of dipeptidyl peptidase-4 (DPP-4), a key regulator of the actions of incretin hormones, exert antihyperglycemic effects in type 2 diabetic patients. A major unanswered question concerns the potential ability of DPP-4 inhibition to have beneficial disease-modifying effects, specifically to attenuate loss of pancreatic beta-cell mass and function. Here, we investigated the effects of a potent and selective DPP-4 inhibitor, an analog of sitagliptin (des-fluoro-sitagliptin), on glycemic control and pancreatic beta-cell mass and function in a mouse model with defects in insulin sensitivity and secretion, namely high-fat diet (HFD) streptozotocin (STZ)-induced diabetic mice. Significant and dose-dependent correction of postprandial and fasting hyperglycemia, HbA(1c), and plasma triglyceride and free fatty acid levels were observed in HFD/STZ mice following 2-3 months of chronic therapy. Treatment with des-fluoro-sitagliptin dose dependently increased the number of insulin-positive beta-cells in islets, leading to the normalization of beta-cell mass and beta-cell-to-alpha-cell ratio. In addition, treatment of mice with des-fluoro-sitagliptin, but not glipizide, significantly increased islet insulin content and improved glucose-stimulated insulin secretion in isolated islets. These findings suggest that DPP-4 inhibitors may offer long-lasting efficacy in the treatment of type 2 diabetes by modifying the courses of the disease.