GSK2798745, a clinical candidate, was identified as an inhibitor of the transient receptor potential vanilloid 4 (TRPV4) ion channel with IC50 of 1.8 and 1.6nM for hTRPV4 and rTRPV4, respectively[1].
In vitro, GSK2798745 (0.3-100nM) inhibited TRPV4 channel activation in a dose-dependent manner following 1h treatment in 293T cells transfected with wild-type or mutant TRPV4[2].
In vivo, Treatment with GSK2798745 at a dose of 10mg/kg by twice daily intraperitoneal injections for 17 days can treat skeletal abnormalities caused by persistent activity of the mutant channel in Col2a1-Cre/Trpv4p.R594H mice[2].
References:
[1] Brooks CA, Barton LS, Behm DJ, et al. Discovery of GSK2798745: A Clinical Candidate for Inhibition of Transient Receptor Potential Vanilloid 4 (TRPV4). ACS Med Chem Lett. 2019;10(8):1228-1233.
[2] Nevarez L, Ismaili TK, Zieba J, et al. Small molecule inhibition rescues the skeletal dysplasia phenotype of Trpv4 mutant mice. JCI Insight. 2026;11(2):e182439.
GSK2798745，一种临床候选药物，被鉴定为瞬时受体电位香草酸受体4（TRPV4）离子通道抑制剂，对人TRPV4和重组TRPV4的IC50值分别为1.8nM和1.6nM[1]。
体外实验中，用野生型或突变型TRPV4转染293T细胞，GSK2798745（0.3-100nM）经1小时处理后，以剂量依赖的方式抑制了TRPV4通道的激活[2]。
体内实验中，对Col2a1-Cre/Trpv4p.R594H小鼠，以10mg/kg的剂量，每日两次腹腔注射GSK2798745，持续17天，可以治疗由突变通道持续活性引起的骨骼异常[2]。