Benzothiazole amide analogues as antagonists of TRPC 6 channels: A therapeutic approach for kidney fibrosis.

Transient receptor potential canonical 6 (TRPC6) channels, which function as receptor-operated, non-selective cation channels, are widely expressed in the kidney, lungs, and brain. Within these organs, they play crucial roles in regulating diverse physiological processes and contribute to the pathogenesis of various disorders. The resolution of the cryo-electron microscopy structure of TRPC6 has significantly advanced our understanding of its molecular mechanisms, thereby providing a robust platform for structure-based drug design. Building upon compound 1S as a lead, we developed and synthesized a series of benzothiazole derivatives, ultimately identifying compound X26 as a potent TRPC6 antagonist with an IC50 of 0.97 μM. In vitro administration of X26 significantly suppressed TGF-β1-induced myofibroblast differentiation in HK-2 cells, as evidenced by a reduced expression of α-SMA, collagen I, and fibronectin. Furthermore, in a unilateral ureteral obstruction (UUO)-induced kidney fibrosis mouse model, treatment with X26 resulted in a substantial reduction in serum urea nitrogen, serum creatinine, and urinary protein levels, as well as a decrease in renal collagen deposition. These findings establish X26 as a promising lead for the development of TRPC6 antagonists and therapeutic interventions for kidney fibrosis.