Original Articles: 2012 Vol: 4 Issue: 6
Preliminary safety evaluation of novel small molecule inhibitors of caspase-3
Caspase inhibition was known to be therapeutically effective in treating the excessive programmed cell death related disorders. We investigated the novel, potent and irreversible small molecules inhibitors of caspase-3 having reasonable selectivity, ADME properties and pharmacologically active compounds for in-vitro cytotoxicity test and in-vivo acute tolerated studies in male balb-c mice. Preliminary safety assessment indicates that maximum safest concentration in the in-vitro test using freshly isolated rat primary hepatocytes was up-to 30µM for all the tested compounds. Interestingly, compound 3D displayed advantage (3fold) in protecting the hepatocytes toxicity when cells were treated with flavopiridol (flavonoid as pan-CDK inhibitor). It also exhibited non-significant changes in behavior of animals, body weight loss, gross pathology, plasma ALT and AST levels when administered orally at 30 mg/kg dose. These results support further development of compound 3D as a potential anti-apoptotic agent.