The glucokinase activator AZD6370 decreases fasting and postprandial glucose in type 2 diabetes mellitus patients with effects influenced by dosing regimen and food

Ericsson, Henrik; Sjöberg, Folke; Heijer, Maria; Dorani, Hassan; Johansson, Peter; Norjavaara, Ensio

doi:10.1016/j.diabres.2012.09.025

Cited by 10 publications

(6 citation statements)

References 22 publications

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“…impaired insulin secretion and excessive hepatic glucose output. [20] To date, 10 GKAs (PF-04937319, [6] MK-0941, [7] AZD1656, [8] dorzagliatin [HMS5532], [10] PF-04991532, [21] piragliatin [RO4389620], [22] AMG 151 [ARRY-403], [23] AZD6370, [24] globalagliatin [LY2608204], [25] and TTP399 [26] ) have undergone clinical trial investigations; however, the results from these studies were not consistent. Due to the obvious heterogeneity among the studies, we developed strict inclusion criteria for a meta-analysis.…”

Section: Discussionmentioning

confidence: 99%

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The efficacy and safety of glucokinase activators for the treatment of type-2 diabetes mellitus

Gao¹,

Zhang²,

Li³

et al. 2021

Medicine

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Background: Glucokinase activators (GKAs) are a novel family of glucose-lowering agents used for the treatment of type-2 diabetes mellitus. Treatment with different GKAs has been shown to reduce blood glucose levels in these patients. We compared the efficacy/safety of GKAs in patients with type-2 diabetes mellitus through a meta-analysis. Methods: We searched the PubMed, Excerpt Medica Database, and Cochrane Central Register of Controlled Trials databases for articles published before December 30, 2020. We computed the weighted mean difference (WMD) and 95% confidence interval (CI) for the change from baseline to the study endpoint for GKA versus placebo treatments. Results: A total of 4 articles (5 studies) were included in the meta-analysis. GKAs were associated with reductions in glycated hemoglobin levels from baseline (WMD, −0.3%; 95% CI, −0.466% to −0.134%). No significant difference between GKA and placebo treatment was observed in the results of fasting plasma glucose levels from baseline (WMD 0.013 mmol/L; 95% CI, −0.304–0.33 mmol/L). A significantly higher change in 2-hour postprandial plasma glucose (2-h PPG) levels (WMD −2.434 mmol/L; 95% CI, −3.304 to −1.564 mmol/L) was observed following GKA than placebo treatment. GKAs were associated with a higher prevalence of causing hypoglycemic events than placebo treatment (risk difference [RD], 0.06; 95% CI 0.013–0.106). GKAs had no association with the risk of developing adverse effects (RD, 0.038; 95% CI, −0.03–0.106) and serious adverse events (RD, 0.01; 95% CI, −0.004–0.023). Conclusions: GKAs were more effective for postprandial blood glucose control. However, these agents showed a significantly high risk of causing hypoglycemia. PROSPERO registration number: CRD42021220364.

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Section: Discussionmentioning

confidence: 99%

“…Due to the obvious heterogeneity among the studies, we developed strict inclusion criteria for a meta-analysis. Many studies were excluded because they did not meet the inclusion criteria [22–24] . In addition, the study involving TTP399, a hepatoselective GKA, was excluded because the results could not be extracted [26] .…”

Section: Discussionmentioning

confidence: 99%

The efficacy and safety of glucokinase activators for the treatment of type-2 diabetes mellitus

Gao¹,

Zhang²,

Li³

et al. 2021

Medicine

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“…AZD-6370 ( Figure 7 ), a GK activator, is being developed by AstraZeneca (London, UK). A dose-ranging, randomised, single-blind, placebo-controlled, crossover assignment phase I study (NCT00690287) was initiated in patients with type 2 diabetes (estimated n = 24) in Sweden 30 . The study was designed to evaluate fasting and postprandial P-glucose levels, safety, and tolerability after the twice- or four times-daily oral administration of AZD-6370.…”

Section: Gkamentioning

confidence: 99%

Glucokinase as an emerging anti-diabetes target and recent progress in the development of its agonists

Ren

Wan

et al. 2022

Journal of Enzyme Inhibition and Medicinal Chemistry

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Type 2 diabetes mellitus is a metabolic disorder with complicated pathogenesis, and mono-target therapy often fails to effectively manage the levels of blood glucose. In recent years, the anti-diabetes target glucokinase (GK) has attracted the attention of researchers. It acts as a glucose sensor, triggering counter regulatory responses following a change in glucose levels to aid restoration of normoglycemia. Activation of GK induces glucose metabolism and reduces glucose levels for the treatment of type 2 diabetes. GK agonists (GKA) are a new class of antidiabetic drugs. Among these agents, dorzagliatin is currently being investigated in phase III clinical trials, while PB-201 and AZD-1656 have reached phase II clinical trials. This article describes the mechanism of action of GK in diabetes and of action of GKA at the protein level, and provides a review of the research, trends, and prospects regarding the use of GKA in this setting.

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“…The literature survey revealed that most of the drug discovery and development research associated with allosteric activators of human GK were mainly focused on the substituted benzamide analogs probably owing to their corresponding alignment outline and bonding connections with the residues of allosteric location of GK (Grewal et al, 2014;Pal et al, 2009b). Some of the benzamide derivatives reported recently as potent GK activators are shown in Figure 1 along with their GK activity (Bowler et al, 2013;Charaya et al, 2018;Ericsson et al, 2012;Grewal et al, 2019aGrewal et al, , 2019bLei et al, 2015;McKerrecher et al, 2018;Park et al, 2013Park et al, , 2014Pike et al, 2011;Sjostrand et al, 2013;Wang et al, 2017). Based on the above-mentioned facts, few newer N-benzothiazol-2-yl benzamide correspondents were proposed as potential activators of human GK.…”

Section: Introductionmentioning

confidence: 99%

Design, synthesis, and evaluation of some novel N-benzothiazol-2-yl benzamide derivatives as allosteric activators of human glucokinase

Sandeep¹,

Grewal²,

Sharma³

et al. 2021

J Appl Pharm Sci

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Some newer benzamide analogues of N-benzothiazol-2-yl were prepared and assessed for human glucokinase (GK) activation accompanied by molecular docking investigations for predicting the bonding connections of the these derivatives with residues in the allosteric site of GK. Among the derivatives synthesized, 6 and 7 strongly increased the catalytic action of GK (GK activation fold about 2.0 compared to control) in vitro. The outcomes of in vitro assay were supported by the molecular docking investigations of these analogues with allosteric site residues of the GK protein. Derivatives investigated in the present study can afford few lead compounds for the discovery of harmless and strong allosteric GK activating compounds for the management of type 2 diabetes.

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The glucokinase activator AZD6370 decreases fasting and postprandial glucose in type 2 diabetes mellitus patients with effects influenced by dosing regimen and food

Cited by 10 publications

References 22 publications

The efficacy and safety of glucokinase activators for the treatment of type-2 diabetes mellitus

The efficacy and safety of glucokinase activators for the treatment of type-2 diabetes mellitus

Glucokinase as an emerging anti-diabetes target and recent progress in the development of its agonists

Design, synthesis, and evaluation of some novel N-benzothiazol-2-yl benzamide derivatives as allosteric activators of human glucokinase

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