Discovery of Alogliptin: A Potent, Selective, Bioavailable, and Efficacious Inhibitor of Dipeptidyl Peptidase IV

Feng, Jinjun; Zhang, Zhiyuan; Wallace, Michael B.; Stafford, Jeffrey A.; Kaldor, Stephen W.; Kassel, Daniel B.; Navre, Marc; Shi, Lihong; Skene, R.J.; Asakawa, Takeshi; Takeuchi, Koji; Xu, Rongda; Webb, David R.; Gwaltney, Stephen L.

doi:10.1021/jm8006799

Cited by 66 publications

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“…39 exhibits a 10,000 times greater preference for DPP IV over the related peptidase DPP VIII and has therapeutic advantages over existing DPP IV inhibitors 102. The inhibitor design was based on docking the cyanoaryl ring of a substituted quinazolinone ( 38 ) into a hydrophobic pocket augmented with hydrogen bonding between the nitrile and an arginine residue 103. X-ray crystallography of a cocrystal structure of 38 in the active site of DPP IV is consistent with the design motif, clearly showing a hydrogen bond from arginine to the nitrile (Figure 12, top).…”

Section: Arylnitrile-containing Pharmaceuticalsmentioning

confidence: 93%

Nitrile-Containing Pharmaceuticals: Efficacious Roles of the Nitrile Pharmacophore

et al. 2010

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Section: Arylnitrile-containing Pharmaceuticalsmentioning

confidence: 93%

Nitrile-Containing Pharmaceuticals: Efficacious Roles of the Nitrile Pharmacophore

et al. 2010

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“…These three formulations of alogliptin were also approved by the European Medicines Agency (EMA) Committee in July 2013. Alogliptin selectively inhibits recombinant human DPP‐4 with an IC 50 of 6.9 nmol/L and has exhibited > 14 000‐fold selectivity over serine proteases DPP‐8 and DPP‐9 (Table ) . This article aims to update our knowledge on the clinical pharmacology of alogliptin used for the treatment of T2DM, with a focus on clinical pharmacodynamics and pharmacokinetics, adverse effects, drug interactions and future directions.…”

Section: Introductionmentioning

confidence: 99%

An update on the clinical pharmacology of the dipeptidyl peptidase 4 inhibitor alogliptin used for the treatment of type 2 diabetes mellitus

Chen

Zhou

et al. 2015

Clin Exp Pharma Physio

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SUMMARYAlogliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor that is a class of relatively new oral hypoglycaemic drugs used in patients with type 2 diabetes (T2DM), can be used as monotherapy or in combination with other anti-diabetic agents, including metformin, pioglitazone, sulfonylureas and insulin with a considerable therapeutic effect. Alogliptin exhibits favorable pharmacokinetic and pharmacodynamic profiles in humans. Alogliptin is mainly metabolized by cytochrome P450 (CYP2D6) and CYP3A4. Dose reduction is recommended for patients with moderate or worse renal impairment. Side effects of alogliptin include nasopharyngitis, upper-respiratory tract infections and headache. Hypoglycaemia is seen in about 1.5% of the T2DM patients. Rare but severe adverse reactions such as acute pancreatitis, serious hypersensitivity including anaphylaxis, angioedema and severe cutaneous reactions such as Stevens-Johnson syndrome have been reported from post-marketing monitoring. Pharmacokinetic interactions have not been observed between alogliptin and other drugs including glyburide, metformin, pioglitazone, insulin and warfarin. The present review aimed to update the clinical information on pharmacodynamics, pharmacokinetics, adverse effects and drug interactions, and to discuss the future directions of alogliptin.

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“…Alogliptin is a potent, highly selective (1), orally available inhibitor of the dipeptidyl peptidase‐4 (DPP‐4) enzyme. DPP‐4 is thought to be primarily responsible for the in vivo degradation of two incretin hormones released in response to nutrient ingestion (2), namely glucagon‐like peptide‐1 (GLP‐1) and glucose‐dependent insulinotropic peptide (GIP).…”

Section: Introductionmentioning

confidence: 99%

Efficacy and safety of adding the dipeptidyl peptidase-4 inhibitor alogliptin to metformin therapy in patients with type 2 diabetes inadequately controlled with metformin monotherapy: a multicentre, randomised, double-blind, placebo-controlled study

Nauck

Ellis²,

Fleck

et al. 2009

International Journal of Clinical Practice

188

160

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Summary Aims: To evaluate the efficacy and safety of alogliptin, a new dipeptidyl peptidase‐4 inhibitor, for 26 weeks at once‐daily doses of 12.5 and 25 mg in combination with metformin in patients whose HbA1c levels were inadequately controlled on metformin alone. Methods and patients: Patients with type 2 diabetes and inadequate glycaemic control (HbA1c 7.0‐10.0%) were randomised to continue a stable daily metformin dose regimen (≥ 1500 mg) plus the addition of placebo (n = 104) or alogliptin at once‐daily doses of 12.5 (n = 213) or 25 mg (n = 210). HbA1c, insulin, proinsulin, C‐peptide and fasting plasma glucose (FPG) concentrations were determined over a period of 26 weeks. Results: Alogliptin at either dose produced least squares mean (SE) decreases from baseline in HbA1c of −0.6 (0.1)% and in FPG of −17.0 (2.5) mg/dl [−1.0 (0.1) mmol/l], decreases that were significantly (p < 0.001) greater than those observed with placebo. The between treatment differences (alogliptin – placebo) in FPG reached statistical significance (p < 0.001) as early as week 1 and persisted for the duration of the study. Overall, adverse events (AEs) observed with alogliptin were not substantially different from those observed with placebo. This includes low event rates for gastrointestinal side effects and hypoglycaemic episodes. There was no dose‐related pattern of AE reporting between alogliptin groups and few serious AEs were reported. Conclusion: Alogliptin is an effective and safe treatment for type 2 diabetes when added to metformin for patients not sufficiently controlled on metformin monotherapy.

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Discovery of Alogliptin: A Potent, Selective, Bioavailable, and Efficacious Inhibitor of Dipeptidyl Peptidase IV

Abstract: 018. Figure 4 depicts a recently obtained cocrystal structure (PDB code 2ONC).

Cited by 66 publications

References 0 publications

Nitrile-Containing Pharmaceuticals: Efficacious Roles of the Nitrile Pharmacophore

Nitrile-Containing Pharmaceuticals: Efficacious Roles of the Nitrile Pharmacophore

An update on the clinical pharmacology of the dipeptidyl peptidase 4 inhibitor alogliptin used for the treatment of type 2 diabetes mellitus

Efficacy and safety of adding the dipeptidyl peptidase-4 inhibitor alogliptin to metformin therapy in patients with type 2 diabetes inadequately controlled with metformin monotherapy: a multicentre, randomised, double-blind, placebo-controlled study

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