噻唑烷二酮类药物作为PPAR调节剂治疗糖尿病的旅程：当前观点。,Current Pharmaceutical Design

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噻唑烷二酮类药物作为PPAR调节剂治疗糖尿病的旅程：当前观点。
Current Pharmaceutical Design ( IF 2.6 ) Pub Date : 2019-07-25 , DOI: 10.2174/1381612825666190716094852
Waquar Ahsan ₁

Affiliation

过氧化物酶体增殖物激活受体（PPAR）也称为格列酮受体，是调节基因表达的一系列受体，除其他功能外，在碳水化合物，脂质和蛋白质代谢中也起着重要作用。PPAR有3种亚型：PPAR-α，PPAR-β/δ和PPAR-γ-PPAR-γ具有2个亚型-γ1和γ2。激活后，PPARs调节涉及脂质和葡萄糖代谢，脂肪细胞分化，增加胰岛素敏感性，防止氧化应激以及在一定程度上通过参与胰岛素发病机制的巨噬细胞对免疫应答的调节的各种基因的转录。抵抗性。因此，PPAR是设计新的抗糖尿病药物的有吸引力的分子靶标。这导致了针对设计PPAR配体的研究工作的增加，特别是可以选择性和特异性激活一种或多种PPAR亚型的配体。尽管PPAR-γ完全激动剂（如噻唑烷二酮类药物（TZDs））是血脂异常和2型糖尿病（T2D）的公认药物，但与TZDs相关的副作用已迫在眉睫，需要找到通过这种药物起作用的新型药物途径。已经使用基于结构的药物设计技术和计算工具设计了几种具有TZD支架的新型衍生物，并测试了它们的PPAR结合亲和力和对抗T2D的功效，其中一些已显示出令人鼓舞的活性。这次审查将着重于PPAR在T2D管理中的作用；

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The Journey of Thiazolidinediones as Modulators of PPARs for the Management of Diabetes: A Current Perspective.

Peroxisome Proliferator-Activated Receptors (PPARs) also known as glitazone receptors are a family of receptors that regulate the expression of genes and have an essential role in carbohydrate, lipid and protein metabolism apart from other functions. PPARs come in 3 sub-types: PPAR-α, PPAR-β/δ and PPAR-γ - with PPAR-γ having 2 isoforms - γ1 and γ2. Upon activation, the PPARs regulate the transcription of various genes involved in lipid and glucose metabolism, adipocyte differentiation, increasing insulin sensitivity, prevention of oxidative stress and to a certain extent, modulation of immune responses via macrophages that have been implicated in the pathogenesis of insulin resistance. Hence, PPARs are an attractive molecular target for designing new anti-diabetic drugs. This has led to a boost in the research efforts directed towards designing of PPAR ligands - particularly ones that can selectively and specifically activate one or more of the PPAR subtypes. Though, PPAR- γ full agonists such as Thiazolidinediones (TZDs) are well established agents for dyslipidemia and type 2 diabetes mellitus (T2D), the side effect profile associated with TZDs has potentiated an imminent need to come up with newer agents that act through this pathway. Several newer derivatives having TZD scaffold have been designed using structure based drug designing technique and computational tools and tested for their PPAR binding affinity and efficacy in combating T2D and some have shown promising activities. This review would focus on the role of PPARs in the management of T2D; recently reported TZD derivatives which acted as agonists of PPAR- γ and its subtypes and are potentially useful in the new drug discovery for the disease.

更新日期：2019-11-01

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