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当前的抗糖尿病药物及其分子靶点:综述。

Current anti-diabetic agents and their molecular targets: A review.

机构信息

School of Chemistry and Physics, University of KwaZulu-Natal, P/Bag X54001, Westville, Durban, South Africa.

School of Chemistry and Physics, University of KwaZulu-Natal, P/Bag X54001, Westville, Durban, South Africa.

出版信息

Eur J Med Chem. 2018 May 25;152:436-488. doi: 10.1016/j.ejmech.2018.04.061. Epub 2018 May 3.

Abstract

Diabetes mellitus is a medical condition characterized by the body's loss of control over blood sugar. The frequency of diagnosed cases and consequential increases in medical costs makes it a rapidly growing chronic disease that threatens human health worldwide. In addition, its unnerving statistical projections are perilous to both the economy of the nation and man's life expectancy. Type-I and type-II diabetes are the two clinical forms of diabetes mellitus. Type-II diabetes mellitus (T2DM) is illustrated by the abnormality of glucose homeostasis in the body, resulting in hyperglycemia. Although significant research attention has been devoted to the development of diabetes regimens, which demonstrates success in lowering blood glucose levels, their efficacies are unsustainable due to undesirable side effects such as weight gain and hypoglycemia. Over the years, heterocyclic scaffolds have been the basis of anti-diabetic chemotherapies; hence, in this review we consolidate the use of bioactive scaffolds, which have been evaluated for their biological response as inhibitors against their respective anti-diabetic molecular targets over the past five years (2012-2017). Our investigation reveals a diverse target set which includes; protein tyrosine phosphatase 1 B (PTP1B), dipeptidly peptidase-4 (DPP-4), free fatty acid receptors 1 (FFAR1), G protein-coupled receptors (GPCR), peroxisome proliferator activated receptor-γ (PPARγ), sodium glucose co-transporter-2 (SGLT2), α-glucosidase, aldose reductase, glycogen phosphorylase (GP), fructose-1,6-bisphosphatase (FBPase), glucagon receptor (GCGr) and phosphoenolpyruvate carboxykinase (PEPCK). This review offers a medium on which future drug design and development toward diabetes management may be modelled (i.e. optimization via structural derivatization), as many of the drug candidates highlighted show promise as an effective anti-diabetic chemotherapy.

摘要

糖尿病是一种人体对血糖失去控制的医学病症。诊断病例的频率以及随之而来的医疗费用增加,使得它成为一种在全球范围内威胁人类健康的快速增长的慢性病。此外,其令人不安的统计预测对国家经济和人类预期寿命都构成了危险。1 型和 2 型糖尿病是糖尿病的两种临床形式。2 型糖尿病(T2DM)表现为体内葡萄糖稳态异常,导致高血糖。尽管人们对糖尿病治疗方案的开发给予了极大关注,这些方案在降低血糖水平方面取得了成功,但由于体重增加和低血糖等不良副作用,其疗效无法持续。多年来,杂环支架一直是抗糖尿病化疗的基础;因此,在这篇综述中,我们总结了过去五年(2012-2017 年)中用于评估其作为各自抗糖尿病分子靶标抑制剂的生物活性支架的使用情况。我们的研究揭示了一个多样化的靶点集,包括:蛋白酪氨酸磷酸酶 1B(PTP1B)、二肽基肽酶-4(DPP-4)、游离脂肪酸受体 1(FFAR1)、G 蛋白偶联受体(GPCR)、过氧化物酶体增殖物激活受体-γ(PPARγ)、钠葡萄糖协同转运蛋白-2(SGLT2)、α-葡萄糖苷酶、醛糖还原酶、糖原磷酸化酶(GP)、果糖-1,6-二磷酸酶(FBPase)、胰高血糖素受体(GCGr)和磷酸烯醇丙酮酸羧激酶(PEPCK)。本综述提供了一个平台,未来的药物设计和开发可以以此为模型(即通过结构衍生化进行优化),因为许多被强调的候选药物都显示出作为有效的抗糖尿病化疗药物的潜力。

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