Athenex Inc., Conventus Building, 1001 Main Street, Suite 600, Buffalo, New York 14203, United States.
Hanmi Pharmaceutical Co. Ltd., 14, Wiryeseong-daero, Songpa-gu, Seoul, 05545, Korea.
J Med Chem. 2021 Apr 8;64(7):3677-3693. doi: 10.1021/acs.jmedchem.0c01826. Epub 2021 Mar 17.
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 (encequidar). Clinically, encequidar was found to be well tolerated and minimally absorbed; and importantly, it enabled the oral delivery of paclitaxel.
许多化疗药物，如紫杉醇，由于肠道上皮细胞的 P-糖蛋白外排机制，口服生物利用度较差，因此需要静脉给药。迄今为止，还没有一种药物被美国食品和药物管理局（FDA）批准，专门针对这种外排泵进行抑制。我们试图寻找一种化合物，选择性地抑制胃肠道黏膜中的 P-糖蛋白，从而避免与全身抑制 P-糖蛋白相关的骨髓毒性等问题。在这里，我们描述了高度有效、选择性和口服生物利用度差的 P-糖蛋白抑制剂（依西奎达）的发现。在临床上，依西奎达被发现具有良好的耐受性和最小的吸收性；更重要的是，它使紫杉醇能够口服给药。
