Medicinal and Process Chemistry Division, Central Drug Research Institute, Lucknow, India.
Department of Chemistry, Lucknow University, Lucknow, India.
Chem Biol Drug Des. 2019 Jul;94(1):1378-1389. doi: 10.1111/cbdd.13515. Epub 2019 Jun 5.
In our continued effort to discover novel PTP1B inhibitor with improved in vivo activity, we attempted to optimize our previously discovered lead compound by replacing the sulfonyl group with benzoyl group to yield compound II. Additional structural modifications were performed on compound II to yield a series of 24 aryl phenylthiazolyl phenylcarboxamides as potential PTP1B inhibitors. Of the 24 tested, 6 compounds showed good PTP1B inhibitory activity while compound 38 as the most promising one. The plausible PTP1B-binding site interaction of compound 38 showed favourable binding similar to known PTP1B binders and suggests its selectivity towards PTP1B. Compound 38 also showed promising antihyperglycaemic, antidyslipidaemic and insulin resistant reversal activities in vivo in STZ model and db/db mice model. Altogether, the compound 38 presents an excellent candidate for future PTP1B targeted drug discovery.
在我们不断努力发现具有改善体内活性的新型 PTP1B 抑制剂的过程中，我们尝试通过用苯甲酰基取代磺酰基来优化我们之前发现的先导化合物，得到化合物 II。在化合物 II 上进行了额外的结构修饰，得到了一系列 24 个芳基苯基噻唑基苯基甲酰胺作为潜在的 PTP1B 抑制剂。在 24 个测试化合物中，有 6 个化合物表现出良好的 PTP1B 抑制活性，其中化合物 38 最为突出。化合物 38 与已知的 PTP1B 结合物具有相似的结合方式，推测其对 PTP1B 具有选择性，其可能的 PTP1B 结合部位相互作用表明。化合物 38 还在 STZ 模型和 db/db 小鼠模型中显示出有希望的抗高血糖、抗脂解和胰岛素抵抗逆转活性。总之，化合物 38 是未来 PTP1B 靶向药物发现的一个极好的候选物。
