Zhang Sicheng, Romero Luis O, Deng Shanshan, Wang Jiaxing, Li Yong, Yang Lei, Hamilton David J, Miller Duane D, Liao Francesca-Fang, Cordero-Morales Julio F, Wu Zhongzhi, Li Wei
Department of Pharmaceutical Sciences, College of Pharmacy, the University of Tennessee Health Science Center, Memphis, Tennessee 38163, United States.
Department of Physiology, the University of Tennessee Health Science Center, Memphis, Tennessee 38163, United States.
ACS Med Chem Lett. 2021 Mar 5;12(4):572-578. doi: 10.1021/acsmedchemlett.0c00571. eCollection 2021 Apr 8.
The overactivation of transient receptor potential canonical 3 (TRPC3) is associated with neurodegenerative diseases and hypertension. Pyrazole 3 (Pyr3) is reported as the most selective TRPC3 inhibitor, but it has two inherent structural limitations: (1) the labile ester moiety leads to its rapid hydrolysis to the inactive Pyr8 , and (2) the alkylating trichloroacrylic amide moiety is known to be toxic. To circumvent these limitations, we designed a series of conformationally restricted Pyr3 analogues and reported that compound maintains high potency and selectivity for human TRPC3 over its closely related TRP channels. It has significantly improved metabolic stability compared with Pyr3 and has a good safety profile. Preliminary evaluation of demonstrated its ability to rescue Aβ-induced neuron damage with similar potency to that of Pyr3 . Collectively, these results suggest that represents a promising scaffold to potentially ameliorate the symptoms associated with TRPC3-mediated neurological and cardiovascular disorders.
瞬时受体电位香草酸亚型3（TRPC3）的过度激活与神经退行性疾病和高血压有关。吡唑3（Pyr3）被报道为最具选择性的TRPC3抑制剂，但它有两个固有的结构局限性：（1）不稳定的酯部分导致其迅速水解为无活性的Pyr8，以及（2）已知烷基化的三氯丙烯酰胺部分具有毒性。为了克服这些局限性，我们设计了一系列构象受限的Pyr3类似物，并报道化合物对人TRPC3与其密切相关的TRP通道相比保持了高效力和选择性。与Pyr3相比，它的代谢稳定性有显著提高，并且具有良好的安全性。对其的初步评估表明，它能够以与Pyr3相似的效力挽救Aβ诱导的神经元损伤。总体而言，这些结果表明，它代表了一个有前景的骨架，有可能改善与TRPC3介导的神经和心血管疾病相关的症状。
