Yu Maolin, Ledeboer Mark W, Daniels Matthew, Malojcic Goran, Tibbitts Thomas T, Coeffet-Le Gal Marie, Pan-Zhou Xin-Ru, Westerling-Bui Amy, Beconi Maria, Reilly John F, Mundel Peter, Harmange Jean-Christophe
Drug Discovery, and Biology, Goldfinch Bio Inc., Cambridge, Massachusetts 02142, United States.
ACS Med Chem Lett. 2019 Oct 22;10(11):1579-1585. doi: 10.1021/acsmedchemlett.9b00430. eCollection 2019 Nov 14.
The nonselective Ca-permeable transient receptor potential (TRP) channels play important roles in diverse cellular processes, including actin remodeling and cell migration. TRP channel subfamily C, member 5 (TRPC5) helps regulate a tight balance of cytoskeletal dynamics in podocytes and is suggested to be involved in the pathogenesis of proteinuric kidney diseases, such as focal segmental glomerulosclerosis (FSGS). As such, protection of podocytes by inhibition of TRPC5 mediated Ca signaling may provide a novel therapeutic approach for the treatment of proteinuric kidney diseases. Herein, we describe the identification of a novel TRPC5 inhibitor, , by systematic optimization of a high-throughput screening hit, pyridazinone . protects mouse podocytes from injury induced by protamine sulfate (PS) . It is also efficacious in a hypertensive deoxycorticosterone acetate (DOCA)-salt rat model of FSGS, significantly reducing both total protein and albumin concentrations in urine.
非选择性钙通透瞬时受体电位（TRP）通道在多种细胞过程中发挥重要作用，包括肌动蛋白重塑和细胞迁移。TRP通道C亚家族成员5（TRPC5）有助于调节足细胞中细胞骨架动力学的紧密平衡，并被认为参与了蛋白尿性肾脏疾病（如局灶节段性肾小球硬化症（FSGS））的发病机制。因此，通过抑制TRPC5介导的钙信号来保护足细胞可能为治疗蛋白尿性肾脏疾病提供一种新的治疗方法。在此，我们描述了通过对高通量筛选命中物哒嗪酮进行系统优化，鉴定出一种新型TRPC5抑制剂 。 可保护小鼠足细胞免受硫酸鱼精蛋白（PS）诱导的损伤。它在FSGS的高血压醋酸脱氧皮质酮（DOCA）-盐大鼠模型中也有效，显著降低尿中总蛋白和白蛋白浓度。
