Discovery of GSK3527497: A Candidate for the Inhibition of Transient Receptor Potential Vanilloid‑4 (TRPV4)

GSK3527497, a preclinical candidate for the inhibition of TRPV4, was identified starting from the previously reported pyrrolidine sulfonamide TRPV4 inhibitors 1 and 2. Optimization of projected human dose was accomplished by specifically focusing on in vivo pharmacokinetic parameters CLu, Vdssu, and MRT. We highlight the use of conformational changes as a novel approach to modulate Vdssu and present results that suggest that molecular-shape-dependent binding to tissue components governs Vdssu in addition to bulk physicochemical properties. Optimization of CLu within the series was guided by in vitro metabolite identification, and the poor FaSSIF solubility imparted by the crystalline properties of the pyrrolidine diol scaffold was improved by the introduction of a charged moiety to enable excellent exposure from high crystalline doses. GSK3527497 is a preclinical candidate suitable for oral and iv administration that is projected to inhibit TRPV4 effectively in patients from a low daily clinical dose.GSK3527497是一款靶向瞬时受体电位阳离子通道亚家族V成员4(TRPV4)的临床前候选化合物，其研发起始于已报道的吡咯烷磺酰胺类TRPV4抑制剂1与2。针对预期人体给药剂量的优化工作，通过专门聚焦于体内药代动力学参数游离清除率(CLu)、游离型稳态分布容积(Vdssu)以及平均滞留时间(MRT)得以完成。本研究重点阐述了将构象变化作为调控Vdssu的全新策略的应用，并展示了相关研究结果：除整体理化性质外，与组织成分的分子形状依赖性结合同样是调控Vdssu的关键因素。该系列化合物的CLu优化以体外代谢物鉴定结果为指导；而吡咯烷二醇骨架的结晶特性所导致的不良空腹模拟肠液(FaSSIF)溶解度，则通过引入带电基团得以改善，从而使得高结晶剂量下可实现优异的体内暴露量。GSK3527497是一款适用于口服与静脉给药的临床前候选化合物，预计可通过较低的每日临床剂量在患者体内实现有效的TRPV4抑制作用。