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

Feng, Jun; 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/jm070104l

Cited by 365 publications

(137 citation statements)

References 14 publications

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“…Studies in an opossum kidney proximal tubule cell line indicate that the enzymatic activity of DPP-4 in the proximal tubular brush border may locally affect the generation or breakdown of endogenous factors that regulate Na ϩ reabsorption via effects on NHE3 activity (17). We tested the renal effects of alogliptin (ALG), a novel, high-affinity, high-specificity DDP-4 inhibitor, in the mouse (5,7,13). We hypothesized that the natriuretic effect of ALG involves inhibition of the breakdown of GLP-1 and, thus, depends on an intact GLP-1R.…”

mentioning

confidence: 99%

Natriuretic effect by exendin-4, but not the DPP-4 inhibitor alogliptin, is mediated via the GLP-1 receptor and preserved in obese type 2 diabetic mice

Rieg

Gerasimova

Murray

et al. 2012

American Journal of Physiology-Renal Physiology

131

111

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Activation of the glucagon-like peptide (GLP)-1 receptor (GLP-1R) and inhibition of dipeptidyl peptidase-4 (DPP-4) are new antidiabetic strategies. The GLP-1R and DPP-4 are also expressed in the renal proximal tubular brush border, where they may regulate Na ϩ reabsorption. Exendin-4 (EX4) is a naturally occurring antidiabetic polypeptide (from the saliva of the lizard Heloderma suspectum) and GLP-1R agonist; however, part of its nonglucoregulatory effects are through GLP-1R-independent mechanisms. DPP-4 cleaves and inactivates GLP-1; thus the natriuretic effect of DPP-4 inhibition may be mediated by the GLP-1R. We report that parenteral application of EX4 in wild-type mice induced a diuresis and natriuresis associated with increases in glomerular filtration rate, fractional urinary fluid and Na ϩ excretion, and renal membrane expression of the Na ϩ /H ϩ exchanger NHE3 phosphorylated at S552 and S605, established consensus sites for cAMP-dependent PKA. These effects were absent in mice lacking the GLP-1R and independent of adenylyl cyclase 6. In comparison, parenteral application of the DPP-4 inhibitor alogliptin reduced plasma DPP-4 activity by 95% and induced a diuresis and natriuresis independent of the presence of the GLP-1R or changes in phosphorylated NHE3. The inhibitory effect on renal fluid and Na ϩ reabsorption of EX4, but not alogliptin, was preserved in diabetic db/db mice and associated with a modest reduction in blood pressure. These results reveal mechanistic differences in how EX4 vs. DPP-4 inhibition induces diuresis and natriuresis under normal states, with preservation of GLP-1R-mediated, but not DPP-4 inhibitor-dependent, natriuretic mechanisms in a mouse model of obese type 2 diabetes.glucagon-like peptide-1; dipeptidyl peptidase-4; NHE3; cAMP; proximal tubule GLUCAGON-LIKE PEPTIDE -1 (GLP-1), an incretin hormone secreted from enteroendocrine L cells in the intestine, stimulates glucose-dependent insulin release and may promote preservation of beta-cell function in patients with type 2 diabetes (9, 10). As a consequence, GLP-1 has been a principal focus of clinical and basic diabetes research in recent years. After secretion, active GLP-1 is rapidly cleaved by the widely expressed enzyme dipeptidyl peptidase-4 (DPP-4, CD26), such that the half-life of bioactive GLP-1 is Ͻ3 min. Therefore, therapeutic manipulation of the GLP-1 system includes strategies that inhibit the degradation of GLP-1 by DPP-4 (i.e., DPP-4 inhibitors) or degradation-resistant GLP-1 receptor (GLP-1R) agonists with a longer half-life, such as exendin-4 (EX4) or liraglutide.In addition to its metabolic effects, GLP-1 affects kidney function. Analysis of GLP-1R expression in rats (6), pigs, and humans (34) localized the GLP-1R to the brush border microvilli of proximal tubules. Intravenous infusion of GLP-1 increased glomerular filtration rate (GFR), inhibited proximal tubular reabsorption, and increased urine flow and Na ϩ excretion in rats (6, 30). In healthy subjects, infusion of GLP-1 evoked a dose-dependent increase in...

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mentioning

confidence: 99%

Natriuretic effect by exendin-4, but not the DPP-4 inhibitor alogliptin, is mediated via the GLP-1 receptor and preserved in obese type 2 diabetic mice

Rieg

Gerasimova

Murray

et al. 2012

American Journal of Physiology-Renal Physiology

131

111

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“…Alogliptin is a potent, selective, bioavailable and efficacious inhibitor of DPP-4 15) . It improves the glycemic control as well as β-cell function, and is well tolerated in type 2 diabetic patients 16,17) .…”

Section: Discussionmentioning

confidence: 99%

“…Likewise, DPP-4 inhibitors also reportedly inhibit atherosclerosis and inflammation in both GLP-1-dependent and -independent manners 14) . Alogliptin is a potent, selective, efficacious and bioavailable inhibitor of DPP-4 15) . Clinical trials have shown that alogliptin improves the glycemic control, as well as β-cell function, and is well tolerated in type (group C) using drugs other than the DPP-4 inhibitor.…”

Section: Introductionmentioning

confidence: 99%

Rationale, Design, and Baseline Characteristics of a Trial for the Prevention of Diabetic Atherosclerosis Using a DPP-4 Inhibitor: The Study of Preventive Effects of Alogliptin on Diabetic Atherosclerosis (SPEAD-A)

Katakami

Mita

Yoshii

et al. 2013

JAT

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Aim: Alogliptin, an efficacious inhibitor of DPP-4 that improves glycemic control, as well as the pancreatic beta-cell function, is now increasingly used to accomplish glycemic targets in type 2 diabetic patients. Interestingly, recent experimental studies have shown that alogliptin exerts anti-atherosclerotic effects in GLP-1-dependent and -independent manners. The aim of the present ongoing study is to investigate the preventive effects of alogliptin on the progression of atherosclerosis in type 2 diabetic subjects using the carotid intima-media thickness (IMT), an established marker of cardiovascular disease. Methods and Results: The Study of Preventive Effects of Alogliptin on Diabetic Atherosclerosis (SPEAD-A

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“…Wistar fatty rats have been used as a good model for evaluation of a number of anti-diabetic drugs, including a biguanide [84], an -glucosidase inhibitor [75], a thiazolidinedione [85], and an DPPIV-i [86].…”

Section: Drug Treatment and Diabetic Complicationsmentioning

confidence: 99%

Non-Obese Type 2 Diabetes Animals Models

Ishii¹,

Ohta²,

Sasase³

2012

Glucose Tolerance

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

Cited by 365 publications

References 14 publications

Natriuretic effect by exendin-4, but not the DPP-4 inhibitor alogliptin, is mediated via the GLP-1 receptor and preserved in obese type 2 diabetic mice

Natriuretic effect by exendin-4, but not the DPP-4 inhibitor alogliptin, is mediated via the GLP-1 receptor and preserved in obese type 2 diabetic mice

Rationale, Design, and Baseline Characteristics of a Trial for the Prevention of Diabetic Atherosclerosis Using a DPP-4 Inhibitor: The Study of Preventive Effects of Alogliptin on Diabetic Atherosclerosis (SPEAD-A)

Non-Obese Type 2 Diabetes Animals Models

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