College of Chemical Engineering, Qingdao University of Science and Technology, Qingdao 266042, China.
School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, China.
J Med Chem. 2023 Feb 23;66(4):3030-3044. doi: 10.1021/acs.jmedchem.2c02003. Epub 2023 Feb 7.
Poor medication adherence in patients with type 2 diabetes mellitus has become one of the main causes of suboptimal glycemic control. Once-weekly drugs can markedly improve the convenience, adherence, and quality of life of T2DM patients; thus, they are clinically needed and preferred. PTP1B plays a negative role in both insulin and leptin signaling pathways, which makes it an important target for diabetes. Herein, we design and synthesize 35 analogues of core BimBH3 peptide lipidation/acylation strategy based on our previous work and evaluate their PTP1B inhibitory activity, obtaining the primary structure-activity relationship. Five compounds with good PPT1B inhibitory activity, target selectivity, and significantly improved stability were selected for molecular docking study and searching candidate molecules with long-acting antidiabetic potential. The anti-T2DM evaluation validated the once-weekly therapeutic potential of analogues , , , , and , which were comparable with semaglutide and therefore presented as promising drug candidates.
2 型糖尿病患者的药物治疗依从性差已成为血糖控制不佳的主要原因之一。每周一次的药物可以显著提高 2 型糖尿病患者的便利性、依从性和生活质量；因此，它们在临床上是需要的和首选的。PTP1B 在胰岛素和瘦素信号通路中起负性作用，使其成为糖尿病的重要靶点。在此，我们基于先前的工作设计并合成了 35 种核心 BimBH3 肽的类似物，采用脂质化/酰化策略，并评估了它们对 PTP1B 的抑制活性，获得了初步的构效关系。选择了 5 种具有良好 PPT1B 抑制活性、靶标选择性和显著改善稳定性的化合物进行分子对接研究，寻找具有长效抗糖尿病潜力的候选分子。抗 2 型糖尿病的评估验证了类似物 、 、 、 和 的每周一次的治疗潜力，它们与司美格鲁肽相当，因此具有成为有前途的药物候选物的潜力。
