1241906-33-1Relevant academic research and scientific papers
Cytochrome P450 Mediated Bioactivation of Saracatinib
Chen, Jiaming,Peng, Ying,Zheng, Jiang
, p. 1835 - 1842 (2017/04/21)
Saracatinib is a highly selective Src kinase inhibitor against all Src kinase family members and has demonstrated anticancer effects in preclinical models. Unfortunately, it has shown multiple adverse effects during its clinical trials, along with time-dependent inhibition of P450 enzymes. The major objective of this study was to identify reactive metabolites of saracatinib in vitro and in vivo. Four oxidative metabolites (M1-M4) were detected in rat and human liver microsomal incubation systems after exposure to saracatinib. An ortho-quinone-derived reactive metabolite existing as a GSH conjugate (M5) was found in microsomes fortified with GSH as a trapping agent. The formation of the metabolites detected was NADPH dependent. Metabolites M2-M4 were also observed in bile and urine of rats given saracatinib, and M5 was only detected in bile. Inhibition and recombinant P450 enzyme incubation studies demonstrated that P450 3A4 was the primary enzyme responsible for the metabolic activation of saracatinib. The metabolism study facilitates the understanding of correlation between saracatinib-induced hepatotoxicity and bioactivation.
Process research and development for the kilogram manufacture of the SRC kinase inhibitor AZD0530
Ford, J. Gair,Pointon, Simon M.,Powell, Lyn,Siedlecki, Paul S.,Baum, John,Chubb, Richard,Fieldhouse, Robin,Muxworthy, James,Nivlet, Alex,Stenson, Rachel,Warwick, Eleanor
, p. 1078 - 1087 (2011/04/12)
Process research and development of a synthetic route towards a novel SRC kinase inhibitor is described. The Medicinal Chemistry route was very long and suffered from extensive use of chlorinated solvents and chromatography. A number of steps in the Medic
