Dose:

Target engagement assay: Potent stimulation of the TRPV4 receptor has catastrophic side effects, as observed when GSK1016790A was administered intravenously to mouse, rat, or dog. Such administration resulted in endothelial failure and circulatory collapse, resulting in a dose-dependent drop in blood pressure and death. In TRPV4-knockout mice, the effect of GSK1016790A on blood pressure, or heart rate, was absent at doses greater than 10-fold the lethal dose in wild-type counterparts, indicating the effect was mediated by TRPV4. Further evaluation in dogs indicated that cardiac output was severely reduced on exposure to GSK1016790A, which was associated with decreased stroke volume and delayed bradycardia. Overall, the catastrophic side effects associated with systemic exposure to a potent TRPV4 agonist, such as GSK1016790A, have resulted in a natural avoidance of such compounds as potential therapeutic agents.