Pribut Nicole, D'Erasmo Michael, Dasari Madhuri, Giesler Kyle E, Iskandar Sabrina, Sharma Savita K, Bartsch Perry W, Raghuram Akshay, Bushnev Anatoliy, Hwang Soyon S, Burton Samantha L, Derdeyn Cynthia A, Basson Adriaan E, Liotta Dennis C, Miller Eric J
Department of Chemistry, Emory University, Atlanta, Georgia 30322, United States.
Yerkes National Primate Research Center, Emory University, Atlanta, Georgia 30329, United States.
J Med Chem. 2021 Sep 9;64(17):12917-12937. doi: 10.1021/acs.jmedchem.1c01083. Epub 2021 Aug 30.
Tenofovir (TFV) is the cornerstone nucleotide reverse transcriptase inhibitor (NtRTI) in many combination antiretroviral therapies prescribed to patients living with HIV/AIDS. Due to poor cell permeability and oral bioavailability, TFV is administered as one of two FDA-approved prodrugs, both of which metabolize prematurely in the liver and/or plasma. This premature prodrug processing depletes significant fractions of each oral dose and causes toxicity in kidney, bone, and liver with chronic administration. Although TFV exalidex (TXL), a phospholipid-derived prodrug of TFV, was designed to address this issue, clinical pharmacokinetic studies indicated substantial hepatic extraction, redirecting clinical development of TXL toward HBV. To circumvent this metabolic liability, we synthesized and evaluated ω-functionalized TXL analogues with dramatically improved hepatic stability. This effort led to the identification of compounds and , which exhibited substantially longer values than TXL in human liver microsomes, potent anti-HIV activity , and enhanced pharmacokinetic properties .
替诺福韦（TFV）是许多为艾滋病毒/艾滋病患者开具的联合抗逆转录病毒疗法中的基石核苷酸逆转录酶抑制剂（NtRTI）。由于细胞通透性差和口服生物利用度低，TFV作为两种经美国食品药品监督管理局（FDA）批准的前药之一给药，这两种前药在肝脏和/或血浆中都会过早代谢。这种前药的过早处理会消耗每次口服剂量的很大一部分，并在长期给药时导致肾脏、骨骼和肝脏毒性。尽管TFV exalidex（TXL），一种TFV的磷脂衍生前药，旨在解决这个问题，但临床药代动力学研究表明其肝脏摄取量大，从而将TXL的临床开发转向了乙型肝炎病毒（HBV）。为了规避这种代谢负担，我们合成并评估了具有显著改善的肝脏稳定性的ω-官能化TXL类似物。这项工作导致鉴定出化合物 和 ，它们在人肝微粒体中的 值比TXL长得多，具有强大的抗艾滋病毒活性 ，并具有增强的药代动力学特性 。
