Discovery of Encequidar, First-in-Class Intestine Specific P‑glycoprotein Inhibitor

Many chemotherapeutics, such as paclitaxel,
are administered intravenously
as they suffer from poor oral bioavailability, partly because of efflux
mechanism of P-glycoprotein in the intestinal epithelium. To date,
no drug has been approved by the U.S. Food and Drug Administration
(FDA) that selectively blocks this efflux pump. We sought to identify
a compound that selectively inhibits P-glycoprotein in the gastrointestinal
mucosa with poor oral bioavailability, thus eliminating the issues
such as bone marrow toxicity associated with systemic inhibition of
P-glycoprotein. Here, we describe the discovery of highly potent,
selective, and poorly orally bioavailable P-glycoprotein inhibitor 14 (encequidar). Clinically, encequidar was found to be well
tolerated and minimally absorbed; and importantly, it enabled the
oral delivery of paclitaxel.