ω-Functionalized Lipid Prodrugs of HIV NtRTI Tenofovir with Enhanced Pharmacokinetic Properties
| Autor: | Anatoliy S. Bushnev, Perry W. Bartsch, Savita Sharma, Kyle E. Giesler, Dennis C. Liotta, Eric J. Miller, Madhuri Dasari, D'erasmo Michael, Adriaan E. Basson, Soyon S. Hwang, Akshay Raghuram, Nicole Pribut, Iskandar Sabrina, Samantha L. Burton, Cynthia A. Derdeyn |
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| Rok vydání: | 2021 |
| Předmět: |
HIV Infections
Pharmacology Antiviral Agents Mice Pharmacokinetics In vivo Drug Discovery medicine Animals Humans Prodrugs Tenofovir Molecular Structure Reverse-transcriptase inhibitor Chemistry Prodrug In vitro Bioavailability Liver Area Under Curve Toxicity Microsome Molecular Medicine Oxidation-Reduction Half-Life medicine.drug |
| Zdroj: | Journal of Medicinal Chemistry. 64:12917-12937 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/acs.jmedchem.1c01083 |
| Popis: | 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 21 and 23, which exhibited substantially longer t1/2 values than TXL in human liver microsomes, potent anti-HIV activity in vitro, and enhanced pharmacokinetic properties in vivo. |
| Databáze: | OpenAIRE |
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