ω-Functionalized Lipid Prodrugs of HIV NtRTI Tenofovir with Enhanced Pharmacokinetic Properties.
ω-Functionalized Lipid Prodrugs of HIV NtRTI Tenofovir with Enhanced Pharmacokinetic Properties.
复制标题
具有增强药代动力学特性的 HIV NtRTI 替诺福韦的α-功能化脂质前药。
DOI：
10.1021/acs.jmedchem.1c01083
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发表时间：
2021
影响因子：
7.3
通讯作者：
M
中科院分区：
文献类型：
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作者：
Pribut,Nicole;D'Erasmo,Michael;Dasari,Madhuri;Giesler,KyleE;Iskandar,Sabrina;Sharma,SavitaK;Bartsch,PerryW;Raghuram,Akshay;Bushnev,Anatoliy;Hwang,SoyonS;Burton,SamanthaL;Derdeyn,CynthiaA;Basson,AdriaanE;Liotta,DennisC;M
替诺福韦（TFV）是治疗HIV/AIDS患者的多种抗逆转录病毒联合疗法中的基础核苷酸逆转录酶抑制剂（NtRTI）。由于细胞渗透性和口服生物利用度差，TFV作为FDA批准的两种前药之一给药，这两种前药都在肝脏和/或血浆中过早代谢。这种过早的前体药物加工消耗了每个口服剂量的显著部分，并在长期给药时引起肾脏、骨骼和肝脏的毒性。虽然TFV exalidex（TXL）是TFV的磷脂衍生前药，旨在解决这一问题，但临床药代动力学研究表明大量肝脏提取，将TXL的临床开发转向HBV。为了避免这种代谢倾向，我们合成并评估了具有显著改善的肝脏稳定性的ω-官能化的TXL类似物。这一努力导致了化合物21和23的鉴定，它们在人肝微粒体中表现出比TXL显著更长的1/2值，体外有效的抗HIV活性，以及增强的体内药代动力学特性。
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 compounds21and23, which exhibited substantially longert1/2values than TXL in human liver microsomes, potent anti-HIV activityin vitro, and enhanced pharmacokinetic propertiesin vivo.