Wang Jiaxing, Zhang Sicheng, Boda Vijay K, Chen Hao, Park Hyunseo, Parmar Keyur, Ma Dejian, Miller Duane D, Meibohm Bernd, Du Jianyang, Liao Francesca-Fang, Wu Zhongzhi, Li Wei
Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, TN 38163, United States.
Department of Anatomy and Neurobiology, University of Tennessee Health Science Center, Memphis, TN 38163, United States; Neuroscience Institute, University of Tennessee Health Science Center, Memphis, TN 38163, United States.
Bioorg Med Chem. 2025 Jan 1;117:118021. doi: 10.1016/j.bmc.2024.118021. Epub 2024 Nov 26.
The TRPC3 protein plays a pivotal role in calcium signaling, influencing cell function. Aberrant TRPC3 expression is implicated in various pathologies, including cardiovascular diseases, tumors, and neurodegeneration. Despite its functional similarities with TRPC6 and TRPC7, TRPC3 exhibits distinct roles in disease contexts. Therefore, it is of paramount importance to develop a potent and selective TRPC3 antagonist with favorable drug-like properties. We employed extensive medicinal chemistry synthesis and structure-activity relationships (SARs) study. Thirty-one novel TRPC3 antagonists were designed and synthesized using the lead compound JW-65 as the scaffold. Compound 60a exhibits a 4-fold improvement in potency and displays exceptional selectivity. With favorable drug-like properties, this compound shows a heightened in vitro neuronal protective effect. Molecular modeling suggests possible modes of action between the TRPC3 protein and its antagonists. In summary, 60a holds significant promise for clinical development in conditions associated with TRPC3 dysregulation.
TRPC3蛋白在钙信号传导中起关键作用，影响细胞功能。TRPC3表达异常与多种病理状况有关，包括心血管疾病、肿瘤和神经退行性变。尽管TRPC3与TRPC6和TRPC7在功能上有相似之处，但在疾病背景下TRPC3发挥着独特作用。因此，开发一种具有良好类药性质的强效且选择性的TRPC3拮抗剂至关重要。我们进行了广泛的药物化学合成和构效关系（SARs）研究。以先导化合物JW-65为骨架设计并合成了31种新型TRPC3拮抗剂。化合物60a的活性提高了4倍，且具有出色的选择性。该化合物具有良好的类药性质，在体外显示出更强的神经元保护作用。分子模拟表明了TRPC3蛋白与其拮抗剂之间可能的作用模式。总之，60a在与TRPC3失调相关的病症临床开发方面具有重大前景。
