Synthesis and biological evaluation of (hetero)arylmethyloxy- and arylmethylamine-phenyl derivatives as potent P-glycoprotein modulating agents

摘要

Starting from lead compounds 12b and 28b, previously characterized as P-glycoprotein (P-gp) modulating agents, two series of new compounds were investigated. Compounds 14a,b and 15a,b displayed high P-gp modulating activity in the submicromolar range (EC50 values from 0.25 to 0.80 mu M). Moreover, amino derivatives 23-27 showed EC50 values ranging from 0.085 to 0.90 mu M. In the pyridyl series, the best result has been obtained for 4-pyridyl derivative 17b (EC50 = 0.85 mu M). The best P-gp modulating agents 14a,b, 15a,b, and 23-27 also have been studied for determining their breast cancer resistance protein (BCRP) inhibition activity. The results demonstrated that only the amino derivatives 23-27 displayed moderate BCRP inhibition activity.