School of Pharmaceutical Sciences, Rajiv Gandhi Proudyogiki Vishwavidyalaya, Airport Bypass Road, Gandhi Nagar, Bhopal, MP 462036, India.
School of Pharmaceutical Sciences, Rajiv Gandhi Proudyogiki Vishwavidyalaya, Airport Bypass Road, Gandhi Nagar, Bhopal, MP 462036, India; Department of Pharmacy, Indira Gandhi National Tribal University, Lalpur, Amarkantak, MP 484887, India.
Bioorg Chem. 2018 Oct;80:145-150. doi: 10.1016/j.bioorg.2018.06.016. Epub 2018 Jun 8.
Described herein is the synthesis and biological evaluation of a series of non-carboxylic inhibitors of Protein Tyrosine Phosphatase 1B designed using bioisosteric replacement strategy. Six N-(3-(1H-tetrazol-5-yl)phenyl)acetamide derivatives designed employing the aforementioned strategy were synthesized and screened for PTP1B inhibitory activity. Among the synthesized compounds, compound NM-03 exhibited the most potent inhibitory activity with IC value of 4.48 µM. Docking studies with NM-03 revealed the key interactions with desired amino acids in the binding site of PTP1B. Furthermore, compound NM-03 also elicited good in vivo activity. Taken together, the results of this study establish N-(3-(1H-tetrazole-5-yl)phenyl)-2-(benzo[d]oxazol-2-ylthio)acetamide (NM-03) as a valuable lead molecule with great potential for PTP1B inhibitor development targeting diabetes.
本文描述了一系列使用生物等排替换策略设计的蛋白酪氨酸磷酸酶 1B 的非羧酸抑制剂的合成和生物学评价。采用上述策略设计的 6 个 N-(3-(1H-四唑-5-基)苯基)乙酰胺衍生物被合成并筛选 PTP1B 抑制活性。在所合成的化合物中，化合物 NM-03 表现出最有效的抑制活性，IC 值为 4.48µM。与 NM-03 的对接研究揭示了与 PTP1B 结合位点中所需氨基酸的关键相互作用。此外，化合物 NM-03 还表现出良好的体内活性。综上所述，这项研究的结果确立了 N-(3-(1H-四唑-5-基)苯基)-2-(苯并[d]恶唑-2-基硫代)乙酰胺（NM-03）作为一种有价值的先导化合物，具有开发针对糖尿病的 PTP1B 抑制剂的巨大潜力。
