Pharmacokinetic profiling of ZCL-278, a cdc42 inhibitor, and its effectiveness against chronic kidney disease
ZCL-278 is a selective small molecule inhibitor that targets the Cdc42-intersectin interaction. However, its pharmacokinetic and pharmacodynamic properties in vivo, particularly in relation to renal diseases, had not been established. Our study aimed to assess the absorption, distribution, and excretion of ZCL-278, as well as its therapeutic potential in chronic kidney disease (CKD). Using an optimized detection method, the oral bioavailability of ZCL-278 was found to be 10.99% in male rats and 17.34% in female rats. The compound was rapidly and widely distributed across various tissues, notably the kidneys and heart, with minimal excretion via urine and feces. In a mouse model of adenine-induced CKD, ZCL-278 significantly improved elevated plasma creatinine and urea levels, body weight loss, and renal pathological changes, such as vacuolization of renal tubular epithelial cells, granular degeneration, cell flattening, luminal dilation, and cylindruria. Additionally, ZCL-278 reversed the heightened renal inflammation and fibrosis observed in CKD mice. These findings provide insight into the pharmacokinetics of ZCL-278 in rats and suggest that it possesses promising pharmacodynamic properties for CKD, supporting its potential for further development as a therapeutic candidate.