Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, BCC, Omaha, NE, 68198, USA; Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Helwan University, Ein-Helwan, Helwan, Cairo, 11795, Egypt; Department of Chemistry, University at Buffalo, The State University of New York, Buffalo, NY, 14260, USA.
Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Helwan University, Ein-Helwan, Helwan, Cairo, 11795, Egypt.
Eur J Med Chem. 2024 Jul 5;273:116492. doi: 10.1016/j.ejmech.2024.116492. Epub 2024 May 11.
Paclitaxel (PTX) is considered the blockbuster chemotherapy treatment for cancer. Paclitaxel's (PTX) oral administration has proven to be extremely difficult, mostly because of its susceptibility to intestinal P-glycoprotein (P-gp) and cytochrome P450 (CYP3A4). The concurrent local inhibition of intestinal P-gp and CYP3A4 is a promising approach to improve the oral bioavailability of paclitaxel while avoiding potential unfavorable side effects of their systemic inhibition. Herein, we report the rational design and evaluation of novel dual potent inhibitors of P-gp and CYP3A4 using an anthranilamide derivative tariquidar as a starting point for their structural optimizations. Compound 14f, bearing N-imidazolylbenzyl side chain, was found to have potent and selective P-gp (EC = 28 nM) and CYP3A4 (IC = 223 nM) inhibitory activities with low absorption potential (P (A-to-B) <0.06). In vivo, inhibitor 14f improved the oral absorption of paclitaxel by 6 times in mice and by 30 times in rats as compared to vehicle, while 14f itself remained poorly absorbed. Compound 14f, possessing dual P-gp and CYP3A4 inhibitory activities, offered additional enhancement in paclitaxel oral absorption compared to tariquidar in mice. Evaluating the CYP effect of 14f on oral absorption of paclitaxel requires considering the variations in CYP expression between animal species. This study provides further medicinal chemistry advice on strategies for resolving concerns with the oral administration of chemotherapeutic agents.
紫杉醇（PTX）被认为是治疗癌症的重磅化疗药物。紫杉醇（PTX）的口服给药已被证明极其困难，主要是因为它容易受到肠道 P 糖蛋白（P-gp）和细胞色素 P450（CYP3A4）的影响。同时抑制肠道 P-gp 和 CYP3A4 是提高紫杉醇口服生物利用度的一种很有前途的方法，同时避免其全身抑制的潜在不利副作用。在此，我们报告了使用蒽酰胺衍生物替利奎达作为结构优化的起点，设计和评估新型双重 P-gp 和 CYP3A4 抑制剂的合理性。带有 N-咪唑基苄基侧链的化合物 14f 被发现对 P-gp（EC = 28 nM）和 CYP3A4（IC = 223 nM）具有很强的选择性抑制作用，吸收潜力低（P（A-to-B）<0.06）。在体内，与载体相比，抑制剂 14f 在小鼠中使紫杉醇的口服吸收增加了 6 倍，在大鼠中增加了 30 倍，而 14f 本身的吸收较差。与替利奎达相比，具有双重 P-gp 和 CYP3A4 抑制活性的化合物 14f 进一步增强了小鼠中紫杉醇的口服吸收。评估 14f 对紫杉醇口服吸收的 CYP 效应需要考虑动物物种之间 CYP 表达的差异。本研究为解决化疗药物口服给药问题提供了进一步的药物化学策略建议。
