Abstract：
Glioblastoma multiforme represents a substantial clinical challenge. Transient receptor potential channel (TRPC) antagonists might provide new therapeutic options for this aggressive cancer. In this study, a series of N-alkyl-N-benzoyl and N-alkyl-N-benzyl thiazoles were designed and prepared using a scaffold-hopping strategy and evaluated as TRPC6 antagonists. This resulted in the discovery of 15g, a potent TRPC antagonist that exhibited suitable inhibitory micromolar activities against TRPC3, TRPC4, TRPC5, TPRC6, and TRPC7 and displayed noteworthy anti-glioblastoma efficacy in vitro against U87 cell lines. In addition, 15g featured an acceptable pharmacokinetic profile and exhibited better in vivo potency (25 mg/kg/d) than the frontline therapeutic agent temozolomide (50 mg/kg/d) in xenograft models. Taken together, the TRPC antagonist 15g represents a promising lead compound for developing new anti-glioblastoma agents.
摘要：
多形性胶质母细胞瘤代表了实质性的临床挑战。瞬时受体电位通道（TRPC）拮抗剂可能为这种侵袭性癌症提供新的治疗选择。在这项研究中,使用支架跳跃策略设计并制备了一系列N-烷基-N-苯甲酰基和N-烷基-N-苄基噻唑,并将其作为TRPC6拮抗剂进行了评估.这导致了15g的发现，一种有效的TRPC拮抗剂，对TRPC3，TRPC4，TRPC5，TPRC6和TRPC7表现出合适的抑制性微摩尔活性，并在体外对U87细胞系表现出值得注意的抗胶质母细胞瘤功效。此外,15g具有可接受的药代动力学特征，并且在异种移植模型中表现出比一线治疗剂替莫唑胺（50mg/kg/d）更好的体内效力（25mg/kg/d）。一起来看,TRPC拮抗剂15g代表了开发新的抗胶质母细胞瘤药物的有前途的先导化合物。
