生物活性

• 靶点	DPP4 IC50:19nM

• 描述The dipeptidyl peptidase 4 (DPP4) is a protein that presenting in various cells of the body and is associated with immune regulation, glucose metabolism and cardiovascular function^[4]. Sitagliptin Phosphate is the phosphate form of Sitagliptin. Sitagliptin, which is used to treat diabetes, is a DPP4 inhibitor with IC50 value of 19 nM^[5]. HLMVECs were treated with sitagliptin with 1000 μM for one hour and the DPP4 activity measured using a CD26/DPPIV Assay kit after four hours of PBS incubation was decreased significantly compared with the control group. The secreated cytokine levels detected by ELISA after LPS (1 μg/ml) for four hours was decreased significantly compared with the cells without sitagliptin treatment^[6]. When sitagliptin was treated with LPS treated (10 μg/ml) H9c2 cells with concentration of 1 μM and above, the cytokines level measured by PCR and ELISA also decreased siginificantly compared with control. The NF-kB level measured by western blotting assay also decreased significantly^[7]. In high salt diet Dahl salt-sensitive rats, sitagliptin was given to the rats orally daily with 10 mg/ kg for eight weeks. The survival rate of the sitagliptin treated group was higher than the control group, and the in situ assessment of DPP4 activity was reduced coupled with an increased expression of GLP-1 receptors from sitagliptin treated group, measured by immunofluorescence labelling and confocal microscopy^[8].
• 作用机制The sitagliptin is a competitive, tight and fast binding inhibitor to the DPP4. It can prolong the bioactivity of the native GLP-1 by inhibiting the proteolytic activity of the DPP4 enzyme^[9].

• 动物研究
  剂量	Rat: 2 mg/kg - 180 mg/kg[3] (p.o.); 0.5 mg/kg - 5 mg/kg[3] (i.v.)
  给药途径	p.o., i.v.
  动物药代数据	Animal Rats[3] Dogs[3] Dose 2 mg/kg (i.v.) 1.5 mg/kg (i.v.) 1.6 mg/kg (p.o.) Administration i.v. or p.o. i.v. or p.o. T1/2 1.8 ± 0.3 h (i.v.) 2.6 ± 0.6 h (p.o.) 4.4 ± 0.1 h (i.v.) 4.5 ± 0.7 h (p.o.) Tmax 2.2 ± 1.8 h (p.o.) 0.8 ± 0.3 h (p.o.) CLp 43 ± 1.3 ml/min/kg (i.v.) 8.9 ± 1.5 ml/min/kg (i.v.) Cmax 0.21 ± 0.13 μM (p.o.) 1.32 ± 0.24 μM (p.o.) Vdss 8.7 ± 3.1 L/kg (i.v.) 3.9 ± 0.8 L/kg (i.v.) AUC0→∞ 1.93 ± 0.06 μM·h (i.v.) 1.17 ± 0.14 μM·h (p.o.) 7.07 ± 1.37 μM·h (i.v.) 7.08 ± 1.52 μM·h (p.o.)

• 临床研究

• NCT号	适应症或疾病	临床期	招募状态	预计完成时间	地点
  NCT00372060	Type 2 Diabetes Mellitus	Phase 3	Completed	-	-
  NCT00372060	-	-	Completed	-	-
  NCT01100125	Diabetes	Phase 4	Completed	-	Korea, Republic of ... more >> Seoul National University Bundang Hospital Seongnam, Gyeonggi, Korea, Republic of, 463-707 Seoul National University Bundang Hospital Seongnam, Korea, Republic of Collapse <<

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• 参考文献

• [1] Sangle GV, Lauffer LM, et al. Novel biological action of the dipeptidylpeptidase-IV inhibitor, sitagliptin, as a glucagon-like peptide-1 secretagogue. Endocrinology. 2012 Feb;153(2):564-73.

  [2] Kim SJ, Nian C, et al. Dipeptidyl peptidase IV inhibition with MK0431 improves islet graft survival in diabetic NOD mice partially via T-cell modulation. Diabetes. 2009 Mar;58(3):641-51.

  [3] JANUVIA

  [4] Salles TA, dos Santos L, Barauna VG, Girardi AC. Potential role of dipeptidyl peptidase IV in the pathophysiology of heart failure. Int J Mol Sci. 2015 Feb 16;16(2):4226-49.

  [5] Röhrborn D, Wronkowitz N, Eckel J. DPP4 in Diabetes. Front Immunol. 2015 Jul 27;6:386.

  [6] Kawasaki T, Chen W, Htwe YM, Tatsumi K, Dudek SM. DPP4 inhibition by sitagliptin attenuates LPS-induced lung injury in mice. Am J Physiol Lung Cell Mol Physiol. 2018 Nov 1;315(5):L834-L845.

  [7] Lin CH, Lin CC. Sitagliptin attenuates inflammatory responses in lipopolysaccharide-stimulated cardiomyocytes via nuclear factor-κB pathway inhibition. Exp Ther Med. 2016 Jun;11(6):2609-2615.

  [8] Esposito G, Cappetta D, Russo R, Rivellino A, Ciuffreda LP, Roviezzo F, Piegari E, Berrino L, Rossi F, De Angelis A, Urbanek K. Sitagliptin reduces inflammation, fibrosis and preserves diastolic function in a rat model of heart failure with preserved ejection fraction. Br J Pharmacol. 2017 Nov;174(22):4070-4086.

  [9] Davis JA, Singh S, Sethi S, Roy S, Mittra S, Rayasam G, Bansal V, Sattigeri J, Ray A. Nature of action of Sitagliptin, the dipeptidyl peptidase-IV inhibitor in diabetic animals. Indian J Pharmacol. 2010 Aug;42(4):229-33.

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