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新型3,5-二取代苯甲酰胺衍生物作为变构葡萄糖激酶激活剂的设计、合成与评价

Design, synthesis and evaluation of novel 3,5-disubstituted benzamide derivatives as allosteric glucokinase activators.

作者信息

Grewal Ajmer Singh, Kharb Rajeev, Prasad Deo Nandan, Dua Jagdeep Singh, Lather Viney

机构信息

1Chitkara College of Pharmacy, Chitkara University, Rajpura, Punjab 140401 India.

2I. K. Gujral Punjab Technical University, Jalandhar, Punjab 144601 India.

出版信息

BMC Chem. 2019 Jan 28;13(1):2. doi: 10.1186/s13065-019-0532-8. eCollection 2019 Dec.

DOI:10.1186/s13065-019-0532-8
PMID:31384754
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6661843/
Abstract

Glucokinase (GK) is the key enzyme expressed in β-cells of pancreas and liver hepatocytes and helps in the maintenance of blood glucose levels in normal range. Activators of GK are the novel category of drug candidates which activate GK enzyme allosterically and show their antidiabetic activity. A new series of 3,5-disubstituted benzamide analogues was designed, synthesized and evaluated as GK activators by in vitro assay as well as in silico docking studies followed by evaluation of antihyperglycemic activity in animal model. Amongst the synthesized derivatives, compounds , , , , and displayed excellent in vitro GK activation. Compounds and exhibited highest antihyperglycemic activity in oral glucose tolerance test in animal model. Compound displayed most significant antihyperglycemic activity and comparable to that of standard drug in animal studies. In addition, antihyperglycemic activity of the synthesized molecules was further supported by the in silico docking studies of the synthesized derivatives in the allosteric site of GK protein.

摘要

葡萄糖激酶（GK）是在胰腺β细胞和肝脏肝细胞中表达的关键酶，有助于将血糖水平维持在正常范围内。GK激活剂是一类新型候选药物，可通过变构方式激活GK酶并显示其抗糖尿病活性。设计、合成了一系列新的3,5-二取代苯甲酰胺类似物，并通过体外试验以及计算机对接研究对其作为GK激活剂进行评估，随后在动物模型中评估其降血糖活性。在合成的衍生物中，化合物 、 、 、 、 和 表现出优异的体外GK激活作用。化合物 和 在动物模型的口服葡萄糖耐量试验中表现出最高的降血糖活性。化合物 在动物研究中表现出最显著的降血糖活性，且与标准药物相当。此外，通过对合成衍生物在GK蛋白变构位点的计算机对接研究，进一步支持了合成分子的降血糖活性。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/acfa/6661843/2c7fbf91841f/13065_2019_532_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/acfa/6661843/33c9c725ab52/13065_2019_532_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/acfa/6661843/fe6472ae59d1/13065_2019_532_Sch1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/acfa/6661843/786e7eecfdec/13065_2019_532_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/acfa/6661843/7eb863904c5c/13065_2019_532_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/acfa/6661843/66febaa93529/13065_2019_532_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/acfa/6661843/2c7fbf91841f/13065_2019_532_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/acfa/6661843/33c9c725ab52/13065_2019_532_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/acfa/6661843/fe6472ae59d1/13065_2019_532_Sch1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/acfa/6661843/786e7eecfdec/13065_2019_532_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/acfa/6661843/7eb863904c5c/13065_2019_532_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/acfa/6661843/66febaa93529/13065_2019_532_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/acfa/6661843/2c7fbf91841f/13065_2019_532_Fig5_HTML.jpg

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