Discovery of a novel pharmacokinetic booster: A small intestine-selective CYP3A4 inhibitor with dibenzyl ether structure.

Abstract

This study describes the development of novel dibenzyl ether derivatives that selectively inhibit intestinal CYP3A4 and are expected to function as pharmacokinetic boosters. Based on previously reported phenylazole derivatives, new compounds were synthesized by systematically modifying the azole moiety, linker structure, and ester functionality to explore structure-activity relationships. The selected dibenzyl ether derivatives exhibited potent CYP3A4 inhibitory activity and remained stable in the presence of intestinal S9 fractions, whereas they were rapidly metabolized in liver S9 fractions to form less active metabolites. The ability to undergo rapid hepatic metabolism is considered advantageous for reducing the risk of drug-drug interactions. These findings suggest that the dibenzyl ether derivatives represent a promising lead for the development of intestine-selective pharmacokinetic booster candidates.