Towards prevention of ischemia-reperfusion kidney injury: Pre-clinical evaluation of 6-chromanol derivatives and the lead compound SUL-138

Eur J Pharm Sci. 2021 Oct 2:106033. doi: 10.1016/j.ejps.2021.106033. Online ahead of print.ABSTRACTAcute Kidney Injury (AKI) is a global healthcare burden attributable to high mortality and staggering costs of dialysis. The underlying causes of AKI include hypothermia and rewarming (H/R), ischemia/reperfusion (I/R), mitochondrial dysfunction and reactive oxygen species production. Inspired by the mechanisms conferring organ protection in hibernating hamster, 6-chromanol derived compounds were developed to address the need of effective prevention and treatment of AKI. Here we report on the pre-clinical screening of 6-chromanol leads that confer protection during I/R to select compounds with favorable profiles for clinical testing in AKI. A library of 6-chromanols (n = 63) was screened in silico for pharmacochemical properties and druggability. Selected compounds (n = 15) were screened for the potency to protect HEK293 cells from H/R cell death and subjected to a panel of in vitro safety assays. Based on these parameters, SUL-138 was selected as the lead compound and was found to safeguard kidney function and decrease renal injury after I/R in rats. The compound was without cardiovascular or respiratory effects in vivo. SUL-138 pharmacokinetics of control animals (mouse, rat) and those undergoing I/R (rat) was identical, showing a two-phase elimination profile with terminal half-life of about 8 h. Collectively, our phenotype-based screening approach led to the identification of...
Source: European Journal of Pharmaceutical Sciences - Category: Drugs & Pharmacology Authors: Source Type: research