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 »  Abstract
 » Introduction
 »  Materials and Me...
 » Results
 » Discussion
 » Acknowledgements
 »  References
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RESEARCH ARTICLE
Year : 2012  |  Volume : 44  |  Issue : 6  |  Page : 759-764
 

Biological evaluation of RBx-0128, a potent and selective dipeptidyl peptidase-IV inhibitor in type 2 diabetes genetic model


1 Department of Pharmacology, New Drug Discovery Research, Ranbaxy Research Laboratories, Gurgaon, Haryana, India
2 Department of Medicinal Chemistry, New Drug Discovery Research, Ranbaxy Research Laboratories, Gurgaon, Haryana, India
3 Department of Metabolism and Pharmacokinetics, New Drug Discovery Research, Ranbaxy Research Laboratories, Gurgaon, Haryana, India

Date of Submission24-Mar-2011
Date of Decision25-Jul-2011
Date of Acceptance31-Aug-2012
Date of Web Publication8-Nov-2012

Correspondence Address:
Joseph A Davis
Department of Pharmacology, New Drug Discovery Research, Ranbaxy Research Laboratories, Gurgaon, Haryana
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0253-7613.103298

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 » Abstract 

Aim: Dipeptidyl peptidase IV (DPP-IV) inhibition to modulate the incretin effect is a proven strategy to treat type 2 diabetes mellitus. The present study describes the pharmacological profile of a novel DPP-IV inhibitor RBx-0128, as an antidiabetic agent.
Material and Methods: DPP-IV assay was carried out to evaluate in vitro potency of RBx-0128 using human, mouse, and rat plasma as an enzyme source. Selectivity was assessed with various serine proteases. In vivo efficacy was assessed in ob/ob mice. The pharmacokinetic (PK) profile was performed in Wistar rats.
Results: RBx-0128 inhibited human, mouse, and rat plasma DPP-IV activity with IC 50 values of 10.6, 18.1, and 56.0 nM respectively, selective over various serine proteases (900-9000-fold). The inhibition was reversible and competitive in nature. In ob/ob mice, RBx-0128 significantly (P < 0.05) inhibited plasma DPP-IV and stimulated GLP-1 and insulin at 10 mg/kg. In the oral glucose tolerance test (OGTT), glucose lowering effect was better than sitagliptin (23 vs. 17%) at 10 mg/kg. The effect was sustained till 8 hours (30-35%) at 10 mg/kg with favorable PK profile (plasma clearance: 39.3 ml/min/kg; Cmax 790 ng/ml; t1/2 1.6 hours; tmax 4.8 hours, Vss 3.24 l/kg and Foral 55%) in Wistar rats.
Conclusions: The present study showed that RBx-0128 is a novel, DPP-IV inhibitor with an antihyperglycemic effect. It can be a promising candidate for the treatment of type 2 diabetes mellitus.


Keywords: Antidiabetic effect, dipeptidyl peptidase-IV inhibitor, glucagon-like peptide-1, oral glucose tolerance test, sitagliptin


How to cite this article:
Davis JA, Kumar PS, Singh S, Surender A, Roy S, Khanna V, Sethi S, Pal C, Sharma L, Benjamin B, Mittra S, Sattigeri J, Bansal VS. Biological evaluation of RBx-0128, a potent and selective dipeptidyl peptidase-IV inhibitor in type 2 diabetes genetic model. Indian J Pharmacol 2012;44:759-64

How to cite this URL:
Davis JA, Kumar PS, Singh S, Surender A, Roy S, Khanna V, Sethi S, Pal C, Sharma L, Benjamin B, Mittra S, Sattigeri J, Bansal VS. Biological evaluation of RBx-0128, a potent and selective dipeptidyl peptidase-IV inhibitor in type 2 diabetes genetic model. Indian J Pharmacol [serial online] 2012 [cited 2021 Oct 21];44:759-64. Available from: https://www.ijp-online.com/text.asp?2012/44/6/759/103298



 » Introduction Top


Type 2 diabetes mellitus is a progressive metabolic disease characterized by impaired glucose tolerance and postprandial hyperglycemia associated with insulin resistance, hyperinsulinemia, and impaired insulin secretion. Currently available oral antidiabetic drugs have limited long-term efficacy and tolerability and are often associated with side effects such as hypoglycemia, weight gain, and nausea. [1] Thus, it is essential to develop safe and orally bioavailable therapeutic agents that would improve glucose homeostasis. One such approach is the use of dipeptidyl peptidase IV (DPP-IV) inhibitors for the treatment of type 2 diabetes. [2] Glucagon-like peptide-1 (GLP-1) is an intestinal peptide hormone secreted from L cells of small intestine in response to food intake. It has been established that GLP-1 plays a crucial role in glucose homeostasis by stimulating insulin synthesis, secretion, and inhibit glucagon release. Further, GLP-1 regulates their functions in a glucose-dependent manner. [3] GLP-1 is considered to be the prime physiological substrate of DPP-IV [4] and its half-life (<2 minutes) is reduced due to rapid inactivation by DPP-IV. This finding prompted the quest for alternative approaches of which DPP-IV inhibitor approach gained prominence with the launch of sitagliptin, vildagliptin, and saxagliptin in several countries and the development of several other potential DPP-IV inhibitors. [5]

DPP-IV (EC 3.4.14.5) is a postproline cleaving serine protease, identical to leukocyte surface antigen CD26, [6] and existing as soluble and membrane bound form. It catalyzes the release of N-terminal dipeptides from biologically active peptides with the preference of proline > hydroxyproline > alanine in the penultimate position [7] DPP-IV has high affinity for GLP-1 and thereby inactivates GLP-1 which can be prevented by DPP-IV inhibitors leading to potentiation of its biological activity. [2] DPP-IV inhibitors have been shown to reduce blood glucose, improve glucose tolerance, and improve insulin responsiveness to oral glucose challenges in animal models. [2],[5] Further, clinical efficacy of advanced DPP-IV inhibitors has been reviewed extensively. [5]

RBx-0128 is a novel DPP-IV inhibitor discovered in our laboratory. [8] The current study was undertaken to biologically evaluate RBx-0128 with respect to in vitro potency, selectivity, mode of inhibition, in vivo efficacy, and pharmacokinetic (PK) profile.


 » Materials and Methods Top


Chemicals

RBx-0128 and sitagliptin were synthesized in the Department of Medicinal Chemistry, Ranbaxy Research Laboratories with >95% purity checked by HPLC analysis. All chemicals were purchased from commercial suppliers: H-glycyl-prolyl-7-amino-4-methylcoumarin (H-Gly-Pro-AMC), Z-glycyl-prolyl-7-amino-4-methylcoumarin (Z-Gly-Pro-AMC) and H-lysyl-prolyl-7-amino-4-methylcoumarin (H-Lys-Pro-AMC) (Bachem AG, Bubendorf, Switzerland); 7-amino-4-methylcoumarin (AMC), H-Ala-Pro-7-amino-trifluoromethyl-coumarin (H-Ala-Pro-AFC), glutaryl-alanyl-alanyl-phenylalanyl-4-methoxy-2-naphthylamine (Glu-MNA), phenylalanyl-proline (Phe-Pro), N#945;-benzoyl-L-arginine-7-amido-4 methyl coumarin, N-succinyl-Ala-Ala-Ala-p-nitroanilide, trypsin and elastase (Sigma-Aldrich); The human recombinant DPP-IV and neutral endopeptidase 24.11 (NEP 24.11) (R & D Systems, Minneapolis, MN); Porcine leucine aminopeptidase (LAP) (Calzyme Inc., USA). DPP-8 and DPP-9 were prepared from crude lysates of CHO cells overexpressing human DPP-8 and DPP-9 and the supernatant obtained from the centrifugation of the lysate were used as enzyme sources. DPP-II was prepared from human seminal plasma after centrifugation and the supernatant was used as enzyme source. Postprolyl cleaving enzyme (PPCE) was prepared from the brain cortex of Wistar rats and the supernatant obtained from the centrifugation of the homogenate was used as enzyme source. Prolidase, aminopeptidase P (APP), and aminopeptidase N (APN) were measured in human plasma. Fibroblast activating protein (FAP) was prepared from human embryonic lung fibroblast lysate and the supernatant obtained from the centrifugation of the homogenate was used as an enzyme source.

Animals

ob/ob mice (8-10 weeks old, either sex) and male Wistar rats (8-10 weeks old) procured from in-house animal breeding facility were provided standard laboratory chow (Harlan Teklad, Oxon, UK) and water ad libitum and maintained on a 12-hour day/night schedule. All experiments were conducted according to the Guidelines of Experimental Animal Care issued by the Committee for Purpose of Control & Supervision of Experiments on Animals (CPCSEA) (Approval No. 84/05 dt. 19/09/2005) and conformed to European Community guidelines.

DPP-IV Enzyme Assay

DPP-IV enzyme assay was performed with either human plasma (10 μl) or human recombinant DPP-IV (10 ng) as described previously by Davis et al. [9]

Selectivity Assays

The selectivity of RBx-0128 was determined against several enzymes such as DPP-II, DPP-8, DPP-9, PPCE, FAP, NEP 24.11, aminopeptidase P, aminopeptidase N, leucine aminopeptidase, prolidase, trypsin, and elastase as described by Shuchita et al. [10]

Relieving of DPP-IV Inhibition

Reversibility of DPP-IV inhibition by RBx-0128 was demonstrated by dissociation experiments. [11] In brief, 10 ng human recombinant DPP-IV were incubated without and with 100 nM RBx-0128 (10-fold excess of its IC 50 value) at 25ºC for 60 minutes. The aliquots were diluted >100-fold into 1 mM H-Gly-Pro-AMC in the assay buffer. The dissociation of the enzyme-inhibitor complex was monitored by substrate hydrolysis by measuring the fluorescence every 30 s for 50 minutes. Blanks were subtracted from the reading and data were analyzed by GraphPad Prism software, Version 4.02 (San Diego, CA).

Competitive Nature of RBx-0128

The IC 50 values of RBx-0128 for DPP-IV inhibition were estimated at different concentrations of H-Gly-Pro-AMC (0, 50, 100, 250, 500, 1000, and 2000 μM) using 10 ng human recombinant DPP-IV as an enzyme source and plotted against the substrate concentrations. The linear response of the IC 50 vs. substrate concentration plot is indicative of competitive nature of the inhibitor. [12]

In vivo Duration of DPP-IV Inhibition by RBx-0128

The ob/ob mice bred in-house were fasted for 16 hours and treated orally with or without RBx-0128 (10 and 20 mg/kg body weight). Blood samples were collected at 0, 60, 120, 240, 480, and 720 minutes from the retro-orbital plexus into tubes containing EDTA. The plasma separated by centrifugation at 3000 rpm for 10 minutes at 4ºC was subjected to DPP-IV activity measurement. The compound was suspended in 0.25 % carboxy methyl cellulose (CMC) vehicle. Control animals were treated with vehicle only. Each group was allocated nine animals.

Efficacy of RBx-0128 in Oral Glucose Tolerance Test Using ob/ob Mice

The overnight-fasted ob/ob mice grouped based on their plasma glucose were administered orally RBx-0128 (10 mg/kg), sitagliptin (10 mg/kg) or vehicle (0.25% CMC) in 10 ml/kg body weight at -30 minutes, followed by oral glucose challenge (2 g/ kg) at 0 minutes. Blood samples collected at 0, 15, 30, 60, and 120 minutes were subjected to plasma glucose measurement using Biochemical Auto Analyzer, Dimension AR (Dade Behring, USA). % AUC of Δblood glucose 0-120 min was calculated from the OGTT curves using GraphPad Prism software, Version 4.02 (GraphPad Software, San Diego, CA).

Effect of RBx-0128 on Insulin and Active GLP-1 Levels

RBx-0128 and sitagliptin at 10 mg/kg were administered orally 30 minutes before oral glucose challenge (2 g/kg) to overnight fasted ob/ob mice. Blood samples collected at 15 and 30 minutes were processed and plasma insulin and GLP-1 (active) concentrations determined with a rat/mouse ELISA kit (LINCO Research Inc, St. Charles, MO, USA). For active GLP-1 measurement, blood samples were collected in tubes containing 10 μM DPP-IV inhibitor supplied by the manufacturer and kept in ice.

Duration of Efficacy of RBx-0128 in The Oral Glucose Tolerance Test Using ob/ob Mice

The overnight fasted ob/ob mice grouped based on their plasma glucose were orally predosed with RBx-0128 (10 mg/ kg) and sitagliptin (10 mg/kg) or vehicle (0.25% CMC) for 8 and 12 hours, followed by oral glucose challenge (2 g/kg). Dose selection was based on the pilot experiment where 0.1, 1, and 10 mg/kg were tested and 10 mg/kg was found to be optimal for both compounds in lowering plasma glucose. Blood samples collected at 0, 15, 30, 60, and 120 minutes were processed and plasma glucose concentrations measured. % AUC of Δblood glucose 0-120 min was calculated from the oral glucose tolerance test curves.

Pharmacokinetic Studies

RBx-0128 was administered to male Wistar rats (8 weeks old) intravenously (i.v.) at 2 mg/kg body weight or orally at 10 mg/kg body weight (n = 3). Blood samples of 300 μl were collected from the jugular vein predose and 0.25, 0.5, 1, 2, 4, 8, 12, and 24-hours postdose in heparin-coated tubes, plasma separated by centrifugation and stored at −80ºC until assayed. The compound concentrations in plasma were determined by LC-MS/MS analysis (API 4000, Applied Biosystems, USA). A calibration curve was constructed ranging from 1 to 1000 ng/ml with 1.08 ng/ml lower level of quantitation. The plasma concentration values were subjected to noncompartmental analysis and the pharmacokinetic parameters estimated.

Statistical Analysis

Data were presented as mean ± S.E.M. The mean IC 50 values and 95% confidence intervals (95% C.I.) were determined from three independent sigmoidal curves of dose-response inhibition of DPP-IV activity by RBx-0128. Differences of DPP-IV inhibition by RBx-0128 at 10 and 20 mg/kg were analyzed by performing one-way Analysis of Variance (ANOVA) followed by Dunnett's multiple comparison test. Differences in blood glucose lowering during the oral glucose tolerance test between vehicle control, RBx-0128, and sitagliptin were determined by ANOVA followed by Dunnett's type multiple comparison test. Differences in active GLP-1 and insulin levels between vehicle control group, RBx-0128, and sitagliptin were analyzed by ANOVA followed by a Bonferroni test. A P value less than 0.05 was considered statistically significant. Statistical analysis was carried out using GraphPad Prism software, Version 4.02.


 » Results Top


DPP-IV Enzyme Inhibition Activity

The inhibitory potency of RBx-0128 on DPP-IV activity was determined in human, mouse, and rat plasma as enzyme sources. RBx-0128 inhibited DPP-IV activity of different species plasma in a dose-dependent manner with IC 50 values of 10.6 nM (human), 18.1 nM (mouse), and 56 nM (rat) [Figure 1]. Sitagliptin inhibited human plasma DPP-IV activity with IC 50 values of 12 nM under experimental conditions.
Figure 1: Dose-response inhibition of DPP-IV by RBx-0128 in human, mouse, and rat. Each point represents the mean ± SEM from experiments performed in triplicate

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Selectivity Assays

The effect of RBx-0128 on several DPP-IV related peptidases including DPP-8 and DPP-9 showed considerable selectivity for DPP-II (~ 900-fold), DPP-8 (~ 1500-fold), DPP-9 (~ 3400-fold) and significant selectivity for PPCE, FAP, NEP 24.11, APP, APN, LAP, prolidase, trypsin and elastase (> 9000-fold) over human DPP-IV inhibition [Table 1].
Table 1: Se lectivity of RBx-0128 against several proline-specifi c proteases

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DPP-IV Inhibition by RBx-0128

DPP-IV activity was blocked by preincubating the human recombinant DPP-IV with 100 nM RBx-0128 (~ 10-fold excess of its IC 50 value). When the preformed enzyme-inhibitor complex was diluted with excess of substrate (> 100-fold that of enzyme-inhibitor concentration), the enzyme activity was recovered in a time-dependent manner [Figure 2]a. In order to characterize the nature of inhibition, when IC 50 values of RBx-0128 determined at different substrate concentrations were plotted against substrate (H-Gly-Pro-AMC) concentrations, IC 50 values increased linearly with substrate concentrations [Figure 2]b.
Figure 2: Binding nature of DPP– IV by RBx-0128. (a) Dissociation of RBx-0128-DPP-IV complex. (b) Competitive nature of RBx-0128. IC50s determined at different concentrations using 10 ng human recombinant DPP-IV enzyme plotted against increasing substrate concentrations. Values are mean ± SEM, n = 3

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In vivo Efficacy of RBx-0128

RBx-0128 inhibited the plasma DPP-IV activity in a time-dependent manner in ob/ob mice, at 10 and 20 mg/kg body weight, though, the DPP-IV inhibition at 20 mg/kg was very significant till 720 minutes compared to control. Comparable DPP-IV inhibition (~ 50%) was exhibited at both doses at 8 hours (480 minutes) followed by a dip at 12 hours (720 minutes) [Figure 3]a. Similarly, as expected, oral administration of RBx-0128 at 10 mg/kg resulted in significant (P < 0.05) plasma glucose lowering compared to vehicle treated groups. The effect was comparable to sitagliptin [Figure 3]b.
Figure 3: Effects of RBx-0128 on DPP-IV activity in plasma (a) and area under curve (AUC). (b) Following oral glucose load (2 g/kg) during the oral glucose tolerance test in ob/ob mice. Values are mean ± SEM, n = 9; ** P < 0.05 compared to the respective vehicle

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Effect of RBx-0128 on Insulin and GLP-1 Levels

RBx-0128 on oral administration at 10 mg/kg in ob/ob mice produce significant (P < 0.05) elevation of both active GLP-1 and insulin compared to vehicle-treated groups at both 15 and 30 minutes [Figure 4]a and b and the effect was comparable to sitagliptin at 10 mg/kg. The secretagogue effects were significantly (P < 0.05) reduced at 30-minute compared to 15-minute treatment.
Figure 4: Effects of RBx-0128 and sitagliptin on active plasma GLP- 1. (a) Insulin, (b) duration of effi cacy. (c) Data are shown as mean ± SEM. P <0.05 compared to respective vehicle, n = 9.

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Efficacy of RBx-0128 in The Oral Glucose Tolerance Test

RBx-0128 exhibited significant (P < 0.05) glucose lowering in ob/ob mice predosed for 8 hours and the effect was comparable to sitagliptin. However, in 12-hour predosing experiments, the glucose lowering effect of RBx-0128 was not significant compared to sitagliptin [Figure 4]c.

Pharmacokinetic Studies

The pharmacokinetic parameters of RBx-0128 followed by a single intravenous administration at 2 mg/kg and single oral administration at 10 mg/kg are shown in [Table 2]. The compound had a terminal half-life of 1.6 hours after intravenous administration. The total clearance and volume of distribution at steady state (Vss ) were 39.3 ml/min/kg and 3.24 l/kg respectively indicating that RBx-0128 is exhibiting moderate plasma clearance and volume of distribution in rats. Following oral administration of RBx-0128, the plasma concentration (Cmax) reached to a maximum of 790 ng/ml with AUC of 2364 ng.hours/ml and oral bioavailability of (Foral) 55%.
Table 2: Details of pharmacokinetic parameters of RBx-0128

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 » Discussion Top


Type 2 diabetes is often associated with impaired insulin and active GLP-1 secretion. [13] Inhibition of DPP-IV in vivo results in elevation of GLP-1 and plasma insulin levels in a glucose-dependent manner thereby causing glucose lowering effect. [2] Several orally active DPP-IV inhibitors are known to lower blood glucose in different animal models. [14] In order to develop DPP-IV inhibitors various facts need to be considered such as unified postproline cleaving activity of DPP-IV sharing with other members of the family with DPP-IV activity and/or structural homolog (DASH) proteins or enzymes, selectivity over several proteases, nature of modulation of multiple physiological substrates and immune function. [14],[15]

The present study identified a novel β amino acid-derived DPP-IV inhibitor, RBx-0128 which inhibited human and rodent DPP-IV effectively. Since, DPP-IV recognizes multiple biological substrates, chronic inhibition of DPP-IV may modulate the bioactivity of these substrates. [4],[16] Interestingly, premarketing surveillance of vildagliptin and postmarketing surveillance of sitagliptin suggested that inhibition of DPP-IV increases the risk of angiodema in patients taking ACE inhibitors. However, it is not clear whether this effect represents a class effect or target effect. [17]

Earlier studies have emphasized the importance of selectivity of DPP-IV inhibitors over other related proteases such as DPP-8, DPP-9, and DPP-II, as their inhibition has been shown to be associated with multiorgan toxicities and mortality in rats. [15] However, chronic DPP8/9 inhibition by vildagliptin (DPP8/9 nonselective inhibitor) [18] as well as 1G244 (DPP8/9 selective inhibitor) [19] did not produce any toxicities in rats suggesting that DPP8/9 inhibition per se does not produce toxicity in rats as reported earlier. [15] RBx-0128 exhibited excellent selectivity against several proteases including DPP-II, DPP-8, DPP-9, PPCE, FAP, NEP 24.11, APP, APN, LAP, prolidase, trypsin, and elastase. Further, RBx-0128 behaved as a competitive inhibitor and the inhibition is reversed by excess substrate suggesting that the compound mediates its biological activity (antidiabetic effect) through binding to the active site of the enzyme. Thus, RBx-0128 appears to be a potent DPP-IV, selective, and competitive inhibitor.

The major focus of DPP-IV inhibitor research is to develop long-acting inhibitors with less dosing frequency. It was hypothesized that long-acting inhibition of DPP-IV may have differential modulating effects on its physiological substrates and the ideal inhibitor should be medium acting. Indeed, the present study showed that RBx-0128 dissociated from the enzyme-inhibitor complex very slowly which may have influence on the duration of DPP-IV inhibitory activity in vivo. In fact, RBx-0128 at 10 mg/kg inhibited plasma DPP-IV activity in ob/ob mice about 40-50% at 8 hours clearly indicating that the inhibitor may exert significant antidiabetic effect at 10 mg/kg up to 8 hours. It has been established that 40-70% of DPP-IV inhibition is well enough to bring the incretin effect. [20] In line with this observation, RBx-0128 inhibited DPP-IV 40-50% at 8 hours and significantly improved glucose lowering in ob/ob mice at 10 mg/kg by oral route and this effect was comparable to sitagliptin at 10 mg/kg dosing regimen. The significant DPP-IV inhibition and antidiabetic activity of RBx-0128 at 8 hours at 10 mg/kg suggest that RBx-0128 can be developed as a medium-acting DPP-IV inhibitor. The augmentation of insulin secretion and glucose-lowering effect by DPP-IV inhibitor in this study could have been mediated by enhanced active GLP-1 levels in plasma and is in agreement with previous reports where DPP-IV inhibition preserved the active GLP-1, augmented insulin response, and improved glucose lowering during oral glucose tolerance test in normal and diabetic animal models. [21],[22],[23] Thus, it can be concluded that RBx-0128 stimulated both active GLP-1 and insulin secretion to bring the glucose lowering effect consistent with its good pharmacokinetic properties in the rat (F = 55 %, CL = 39.3 ml/min/kg, tmax = 4.8 h, Cmax = 790 ng/ml).

In conclusion, RBx-0128 is a potent, selective, competitive, and reversible DPP-IV inhibitor regulating glucose homeostasis through stimulation of active GLP-1 and insulin secretion. The results suggest that RBx-0128 can be developed as medium-acting DPP-IV inhibitor to treat type 2 diabetes mellitus.


 » Acknowledgements Top


The authors would like to thank Drs. Abhijit Ray (Director, Pharmacology, NDDR), Ian A Cliff (Director, Medicinal Chemistry, NDDR), Pradipkumar Bhatnagar (Senior Vice-President, NDDR) for their valuable suggestions.

 
 » References Top

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10.Singh S, Roy S, Sethi S, Benjamin B, Sundaram S, Khanna V, et al. RBx-0597, a potent, selective and slow-binding inhibitor of dipeptidyl peptidase-IV for the treatment of type 2 diabetes. Eur J Pharmacol 2011;652:157-63.  Back to cited text no. 10
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20.Augeri DJ, Robl JA, Betebenner DA, Magnin DR, Khanna A, Robertson JG. et al. Discovery and preclinical profile of saxagliptin (BMS-477118): A highly potent, long-acting, orally active dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes. J Med Chem 2005;48:5025-37.  Back to cited text no. 20
    
21.Kim D, Wang L, Beconi M, Eiermann GJ, Fisher MH, He H, et al. (2 R)-4-Oxo-4-[3-(Trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8 H)-1-(2,4,5-trifluorophenyl)butan-2-amine: A potent, orally active dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes. J Med Chem 2005;48:141-51.  Back to cited text no. 21
    
22.Villhauer EB, Brinkman JA, Naderi GB, Burkey BF, Dunning BE, Prasad K, et al. 1-[[(3-Hydroxy-1-adamantyl)amino]acetyl]-2-cyano-(S)-pyrrolidine: A potent, selective, and orally bioavailable dipeptidyl peptidase IV inhibitor with antihyperglycemic properties. J Med Chem 2003;46:2774-89.  Back to cited text no. 22
    
23.Pederson RA, White HA, Schlenzig D, Pauly RP, McIntosh CH, Demuth HU. Improved glucose tolerance in Zucker fatty rats by oral administration of the dipeptidyl peptidase IV inhibitor isoleucine thiazolidide. Diabetes 1998;47:1253-8.  Back to cited text no. 23
    


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4]
 
 
    Tables

  [Table 1], [Table 2]



 

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