Alogliptin Benzoate

Alogliptin is a novel, highly selective and potent inhibitor of serine protease dipeptidylpeptidase-4 (DPP-4) with IC50 value of less than 10 nM [1].

Alogliptin has been reported to significantly reduce plasma DPP-4 activity and increase active GLP-1 levels in a dose-dependent manner in ob/ob mice. Besides, alogliptin after 4 weeks administration remarkably reduced non-fasting glycosylated hemoglobin, non-fasting plasma glucose and triglyceride levels, as well as siginificantly increased non-fasting plasma insulin and fasting pancreatic insulin content in ob/ob mice. Moreover, alogliptin treated ob/ob mice have shown the increase of early-phase insulin secretion and the decrease of plasma glucose AUC [2]

References:
[1] Feng J, Zhang Z, Wallace MB, Stafford JA, Kaldor SW, Kassel DB, Navre M, Shi L, Skene RJ, Asakawa T, Takeuchi K, Xu R, Webb DR, Gwaltney SL 2nd. Discovery of alogliptin: a potent, selective, bioavailable, and efficacious inhibitor of dipeptidyl peptidase IV. J Med Chem. 2007 May 17;50(10):2297-300.
[2] Moritoh Y1, Takeuchi K, Asakawa T, Kataoka O, Odaka H. Chronic administration of alogliptin, a novel, potent, and highly selective dipeptidyl peptidase-4 inhibitor, improves glycemic control and beta-cell function in obese diabetic ob/ob mice. Eur J Pharmacol. 2008 Jul 7;588(2-3):325-32.

Alogliptin benzoate for management of type 2 diabetes.[Pubmed:25914541]

Vasc Health Risk Manag. 2015 Apr 10;11:229-43.

Dipeptidyl peptidase-4 (DPP-4) inhibitors, a new class of oral hypoglycemic agents, augment glucose-dependent insulin secretion and suppress glucagon levels through enhancement of the action of endogenous incretin by inhibiting DPP-4, an incretin-degrading enzyme. DPP-4 inhibitors are generally well tolerated because of their low risk of hypoglycemia and other adverse events. Moreover, with their potential to improve beta cell function, a core defect of type 2 diabetes, DPP-4 inhibitors are becoming a major component of treatment of type 2 diabetes. Alogliptin Benzoate is a newly developed, highly selective DPP-4 inhibitor which has been approved in many countries throughout the world. Once-daily administration of alogliptin as either monotherapy or combination therapy with other oral antidiabetic drugs or insulin has a potent glucose-lowering effect which is similar to that of other DPP-4 inhibitors, with a low risk of hypoglycemia and weight gain. The cardiovascular safety of this drug has been confirmed in a recent randomized controlled trial. This review summarizes the efficacy and safety of alogliptin, and discusses the role of DPP-4 inhibitors in the treatment of type 2 diabetes.

Alogliptin benzoate for the treatment of type 2 diabetes.[Pubmed:24646052]

Expert Opin Pharmacother. 2014 Apr;15(6):851-63.

INTRODUCTION: Type 2 diabetes mellitus continues to be a global problem, placing an enormous burden on healthcare systems and resources. Effective treatment options to minimize the effects of hyperglycemia are essential. Most patients eventually need to take multiple drugs to maintain glycemic control, and many antidiabetic drugs are associated with adverse effects, such as hypoglycemia, weight gain or gastrointestinal effects. Dipeptidyl peptidase (DPP)-4 inhibitor is one of the newer classes of oral antidiabetic drug, and alogliptin is the most recently approved drug in this class. AREAS COVERED: This paper reviews the pharmacodynamic and pharmacokinetic properties of alogliptin and the results of clinical trials evaluating its efficacy at improving glycemic control in patients with type 2 diabetes both as monotherapy and in combination with other antidiabetic drugs. The drug's tolerability and safety profiles are also considered. EXPERT OPINION: Alogliptin is a DPP-4 inhibitor that can help in improving glycemic control in patients with type 2 diabetes, including the elderly. It is generally well tolerated and does not increase the risk of hypoglycemia or weight gain.

Degradation Kinetics Study of Alogliptin Benzoate in Alkaline Medium by Validated Stability-Indicating HPTLC Method.[Pubmed:27608919]

J AOAC Int. 2016 Nov 1;99(6):1505-1512.

A rapid, sensitive, and stability-indicating high-performance thin-layer chromatographic method was developed and validated to study degradation kinetics of Alogliptin Benzoate (ALG) in an alkaline medium. ALG was degraded under acidic, alkaline, oxidative, and thermal stress conditions. The degraded samples were chromatographed on silica gel 60F254-TLC plates, developed using a quaternary-solvent system (chloroform-methanol-ethyl acetate-triethyl amine, 9+1+1+0.5, v/v/v/v), and scanned at 278 nm. The developed method was validated per International Conference on Harmonization guidelines using validation parameters such as specificity, linearity and range, precision, accuracy, LOD, and LOQ. The linearity range for ALG was 100-500 ng/band (correlation coefficient = 0.9997) with an average recovery of 99.47%. The LOD and LOQ for ALG were 9.8 and 32.7 ng/band, respectively. The developed method was successfully applied for the quantitative estimation of ALG in its synthetic mixture with common excipients. Degradation kinetics of ALG in an alkaline medium was studied by degrading it under three different temperatures and three different concentrations of alkali. Degradation of ALG in the alkaline medium was found to follow first-order kinetics. Contour plots have been generated to predict degradation rate constant, half-life, and shelf life of ALG in various combinations of temperature and concentration of alkali using Design Expert software.

Isolation and characterization of related substances in alogliptin benzoate by LC-QTOF mass spectrometric techniques.[Pubmed:27281581]

J Pharm Biomed Anal. 2016 Sep 5;128:253-263.

A highly specific and efficient LC-QTOF mass spectrometric method was developed for the separation and characterization of process related substances and the major degradation products in Alogliptin Benzoate and its tablets. The separation was performed on Phenomenex Gemini-NX C18 column (250mmx4.6mm, 5mum) using 0.2% formic acid-0.2% ammonium acetate in water as mobile phase A, acetonitrile and methanol (60:40, v/v) as mobile phase B in linear gradient elution mode. Forced degradation studies were also conducted under ICH prescribed stress conditions. Alogliptin Benzoate and its tablets were tending to degrade under acid, alkaline, oxidative and thermal stresses, while relatively stable to photolytic stress. A total of seven related substances were detected and characterized through liquid chromatography-high resolution QTOF mass spectrometry techniques, including process related substances and degradation products, and two of them were further synthesized and characterized by NMR spectroscopy. Based on the related substances elucidation and the plausible formation mechanisms, efficient approaches were proposed to reduce or eliminate related substances, and in consequence the quality of Alogliptin Benzoate and its tablets have been promoted obviously. Therefore, the impurity profiles obtained are critical to the quality control and manufacturing processes optimization and monitoring of Alogliptin Benzoate and its tablets.

Alogliptin benzoate(SYR 322) is a potent, selective inhibitor of DPP-4 with IC50 of <10 nM, exhibits greater than 10,000-fold selectivity over DPP-8 and DPP-9.

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