N-pyridin-2-yl benzamide analogues as allosteric activators of glucokinase: Design, synthesis, in vitro, in silico and in vivo evaluation.,Chemical Biology & Drug Design

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N-pyridin-2-yl benzamide analogues as allosteric activators of glucokinase: Design, synthesis, in vitro, in silico and in vivo evaluation.
Chemical Biology & Drug Design ( IF 3.2 ) Pub Date : 2018-11-28 , DOI: 10.1111/cbdd.13423
Ajmer Singh Grewal _{1,

2} , Rajeev Kharb ₃ , Deo Nandan Prasad ₄ , Jagdeep Singh Dua ₄ , Viney Lather _{3,

5}

Affiliation

Glucokinase (GK) is the key enzyme controlling levels of blood glucose under normal physiological range, and GK activators are emerging class of drug candidates with promising hypoglycaemic activity. The current study was planned to design, synthesize and evaluate novel N-pyridin-2-yl benzamide analogues as allosteric activators of GK. A novel series of N-pyridin-2-yl benzamide analogues were synthesized starting from 3-nitrobenzoic acid and evaluated in vitro for GK activation followed by in silico studies to predict the binding interactions of the designed molecules with GK protein. The selected synthesized molecules (compounds 5b, 5c, 5e, 5g, 5h and 6d) which displayed excellent GK activity (GK fold activation around 2) in GK assay and appreciable binding interaction with GK in docking studies were further evaluated for their antihyperglycaemic potential using oral glucose tolerance test (OGTT) in rats. Amongst the compounds tested in vivo (OGTT assay) for antihyperglycaemic potential, compounds 5c, 5e and 5g displayed significant reduction in blood glucose levels. Compound 5e displayed most significant antidiabetic activity and comparable to that of standard drug in animal studies. The N-pyridin-2-yl benzamide analogues discovered in the current study can provide some lead molecules for the development of potent oral GK activators with minimum side-effects for the management of type 2 diabetes.

中文翻译：

N-吡啶-2-基苯甲酰胺类似物作为葡萄糖激酶的变构活化剂：设计，合成，体外，计算机和体内评估。

葡萄糖激酶（GK）是在正常生理范围内控制血糖水平的关键酶，GK激活剂是新兴的候选类药物，具有良好的降血糖活性。目前的研究计划设计，合成和评估新型N-吡啶-2-基苯甲酰胺类似物作为GK的变构活化剂。从3-硝基苯甲酸开始合成一系列新的N-吡啶-2-基苯甲酰胺类似物，并在体外评估GK活化，然后进行计算机研究以预测设计分子与GK蛋白的结合相互作用。选定的合成分子（化合物5b，5c，5e，5g，使用口服葡萄糖耐量试验（OGTT）在大鼠中进一步评估了在GK分析中显示出优异的GK活性（大约2的GK倍数活化）和在对接研究中与GK产生明显结合相互作用的5h和6d）。在体内测试的化合物（OGTT分析）具有抗高血糖的潜力，化合物5c，5e和5g显示出血糖水平的显着降低。在动物研究中，化合物5e显示出最显着的抗糖尿病活性，与标准药物相当。在本研究中发现的N-吡啶-2-基苯甲酰胺类似物可为开发有效的口服GK激活剂提供一些先导分子，而对2型糖尿病的治疗副作用则最小。在体内测试的化合物（OGTT分析）具有抗高血糖的潜力，化合物5c，5e和5g显示出血糖水平的显着降低。在动物研究中，化合物5e显示出最显着的抗糖尿病活性，与标准药物相当。在当前研究中发现的N-吡啶-2-基苯甲酰胺类似物可以为开发有效的口服GK激活剂提供一些先导分子，而对2型糖尿病的治疗副作用则最小。在体内测试的化合物（OGTT分析）具有抗高血糖的潜力，化合物5c，5e和5g显示出血糖水平的显着降低。在动物研究中，化合物5e显示出最显着的抗糖尿病活性，与标准药物相当。在当前研究中发现的N-吡啶-2-基苯甲酰胺类似物可以为开发有效的口服GK激活剂提供一些先导分子，而对2型糖尿病的治疗副作用则最小。

更新日期：2018-11-28

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