Abstract
The ATP-binding cassette sub-family G member 2 (ABCG2) plays an important role in modulating drug disposition and endobiotic homeostasis. KO143 is a potent and relatively selective ABCG2 inhibitor. We found that the metabolic stability of KO143 was very poor in human liver microsomes (HLM). Our further studies illustrated that the tert-butyl ester group in KO143 can be rapidly hydrolyzed and removed by carboxylesterase 1. This metabolic pathway was confirmed as a major pathway of KO143 metabolism in both HLM and mice. K1 is an analog of KO143 without the ester group. We found that the metabolic stability of K1 was significantly improved in HLM when compared to KO143. These data suggest that the ester group in KO143 is the major cause of the poor metabolic stability of KO143. The data from this study can be used to guide the development of KO143 analogs with better metabolic properties.