Abstract
Acute 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 3 candidates for pre-clinical studies (5%, 3/64). SUL-138 emerged from this small-scale library of 6-chromanols as a novel prophylactic for AKI. The presented efficacy and safety data provide a basis for future development and clinical testing. Section assignments: Drug discovery and translational medicine, renal, metabolism Significance statement: Based on in silico druggability parameters, a 63 compound 6-chromanol library was narrowed down to 15 compounds. These compounds were subjected to phenotypical screening of cell survival following hypothermia damage and hit compounds were identified. After subsequent assessment of in vivo efficacy, toxicity, pharmacokinetics, and cardiovascular and respiratory safety, SUL-138 emerged as a lead compound that prevented kidney injury after ischemia/reperfusion and demonstrated a favorable pharmacokinetic profile unaffected by renal ischemia.
Highlights
Acute kidney Injury (AKI) remains a growing global healthcare challenge
To advance hits for potential human use, the compounds were screened based on their chemical descriptors including molecular weight, parti tion coefficients (ClogP), and the Lipinski rule of five for oral drugs (Benet et al, 2016) (Table 1) to determine a subset of candidates for Trolox Abbreviation used for new 6-chromanols (SUL)-95 SUL-109 SUL-121 SUL-122 SUL-125 SUL-128 SUL-131 SUL-132 SUL-134 SUL-135 SUL-137 SUL-138 SUL-139 SUL-141 SUL-142
The two most potent compounds SUL-121 and SUL138 were preferred over SUL-122 (EC50 = 12.59 nM) and SUL-125 (EC50 = 144.54 nM) mainly on the basis of in vitro efficacy in protect ing Human Embryonic Kidney Cells (HEK293) cells from hypothermia and rewarming (H/R)-induced death
Summary
Acute kidney Injury (AKI) remains a growing global healthcare challenge. The International Society of Nephrology estimates 13.3 million new AKI cases and 1.7 million deaths worldwide each year (International Society of Nephrology. n.d.). In England and the USA, the annual costs of AKI-related hospitalization are estimated at £1.02 billion and $23.9 billion, respectively (Kerr et al, 2014). Both the patient burden and the staggering costs of AKI treatment are largely attributable to renal replacement therapy, e.g., hemodialysis (Collister et al, 2017). AKI patients undergoing renal replacement therapy suffer high mortality rates (Levey and James, 2017). This substantiates a dire need for adequate prevention and pharmacotherapy of AKI
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