Synthesis and Biological Evaluation of Xanthine Derivatives on Dipeptidyl Peptidase 4

Lin, Kwei-Jay; Cai, Zengxuan; Wang, Fei; Zhang, Wei; Zhou, Weicheng

doi:10.1248/cpb.c12-01046

Cited by 12 publications

(6 citation statements)

References 12 publications

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“…98 Xanthine-based compounds were also developed, resulting in compounds with 1−30 μM IC 50 values and acceptable selectivity versus the other peptidases of the DPP IV family. 99 Therefore, docking-based approaches resulted in DPP IV inhibitors that were very selective for this enzyme compared to DPP-8 and DPP-9 but with low inhibition potency. However, it can be postulated that pursuing these lead molecules may result in potentially interesting therapeutics for further clinical development.…”

Section: ■ More Recent Dpp IV Inhibitors Under Developmentmentioning

confidence: 99%

Dipeptidyl Peptidase IV and Its Inhibitors: Therapeutics for Type 2 Diabetes and What Else?

2013

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The proline-specific dipeptidyl aminopeptidase IV (DPP IV, DPP-4, CD26), widely expressed in mammalians, releases X-Pro/Ala dipeptides from the N-terminus of peptides. DPP IV is responsible of the degradation of the incretin peptide hormones regulating blood glucose levels. Several families of DPP IV inhibitors have been synthesized and evaluated. Their positive effects on the degradation of the incretins and the control of blood glucose levels have been demonstrated in biological models and in clinical trials. Presently, several DPP IV inhibitors, the "gliptins", are approved for type 2 diabetes or are under clinical evaluation. However, the gliptins may also be of therapeutic interest for other diseases beyond the inhibition of incretin degradation. In this Perspective, the biological functions and potential substrates of DPP IV enzymes are reviewed and the characteristics of the DPP IV inhibitors are discussed in view of type 2 diabetes and further therapeutic interest.

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Section: ■ More Recent Dpp IV Inhibitors Under Developmentmentioning

confidence: 99%

Dipeptidyl Peptidase IV and Its Inhibitors: Therapeutics for Type 2 Diabetes and What Else?

2013

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“…It has been shown that linagliptin, DPP-4 inhibitor with xanthine-based structure ( Figure 2) and reported IC50 value of ~ 1 nM (13)(14)(15)(16), at the oral dose of 5 mg/kg for 7 days normalized increased serum XO activity in septic rats (17). Additionally, linagliptin exerted an inhibitory effect on the activity of XO in vitro and in human serum derived from the healthy volunteer in a concentration-dependent manner up to 1 mM, as well as lowered uric acid levels in plasma of diabetic patients at the oral dose of 5 mg once daily for 24 weeks (18).…”

Section: Linagliptin Dipeptidyl Peptidase-4 and Xanthine Oxidase Inhmentioning

confidence: 99%

“…Some DPP-4 inhibitors (13)(14)(15)(16)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28) have been derived from a xanthine scaffold, similar to the structure of linagliptin (Table 1, Figure 3). 61 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 61 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 ...…”

Section: Overview Of Purine-based Dpp-4 Inhibitorsmentioning

confidence: 99%

Potential Dual Mechanism of Hypouricemicactivity of DPP-4 Inhibitors With Purine-Based Scaffold

Tomovic¹,

Kocić²,

Šmelcerović³

2019

AMM

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Dipeptidyl peptidase-4 (DPP-4) binds to adenosine deaminase (ADA) and form a complex which catalyzes an irreversible deamination of extracellular adenosine to inosine, what leads to the generation of hypoxanthine, xanthine and finally uric acid by xanthine oxidase (XO) in purine catabolism with the production of reactive oxygen species. Xanthine-based DPP-4 inhibitor linagliptin showed inhibitory potential on XO. It exerts a hypouricemic effect by inhibiting DPP-4 activity and its binding to ADA, what causes the increase of adenosine and decrease of XO substrates levels, as well as by inhibiting XO activity. Based on the evidenced dual mechanism of hypouricemic activity of linagliptin, the possibility of other DPP-4 inhibitors with the purine-based scaffold to act in the same manner exists.

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“…Many synthetic analogs of alogliptin by replacing the cyanobenzyl group with the butynyl group have been synthesized and tested as selective DPP‐4 inhibitors . Additionally, quinazolines , pyridopyrimidinedione , pyrazolopyrimidinones , and pyrimidine as DPP‐IV inhibitors are of particular interest in this field. Furthermore, various quinazoline, thiazoline, and quinazoline clubbed thiazoline analogues proved to be effective antidiabetic agents (Fig.…”

Section: Introductionmentioning

confidence: 99%

Design, Synthesis, and Biological Evaluation of Novel Quinazoline Clubbed Thiazoline Derivatives

Ali

Akhtar

Siddiqui

et al. 2017

Archiv der Pharmazie

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A novel series of quinazoline clubbed thiazoline derivatives was rationally designed and synthesized. The newly synthesized compounds were evaluated for in vitro dipeptidyl peptidase IV (DPP-4) inhibitory activity. Compounds that showed good to moderate activity were compared using linagliptin as standard. Compound 4x (IC = 1.12 nM) exhibited the most promising results. The special chemical feature of compound 4x also imparts good inhibition selectivity for DPP-4 over DPP-8/9. Moreover, docking of compound 4x into the active site of DPP-4 illustrates its possible binding interactions.

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Synthesis and Biological Evaluation of Xanthine Derivatives on Dipeptidyl Peptidase 4

Cited by 12 publications

References 12 publications

Dipeptidyl Peptidase IV and Its Inhibitors: Therapeutics for Type 2 Diabetes and What Else?

Dipeptidyl Peptidase IV and Its Inhibitors: Therapeutics for Type 2 Diabetes and What Else?

Potential Dual Mechanism of Hypouricemicactivity of DPP-4 Inhibitors With Purine-Based Scaffold

Design, Synthesis, and Biological Evaluation of Novel Quinazoline Clubbed Thiazoline Derivatives

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