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Your search keyword '"Perry W. Bartsch"' showing total 2 results
Start Over Author "Perry W. Bartsch" Topic tenofovir
2 results on '"Perry W. Bartsch"'

1. Expanding the toolbox of metabolically stable lipid prodrug strategies

Author

Kiran S. Toti, Nicole Pribut, Michael D’Erasmo, Madhuri Dasari, Savita K. Sharma, Perry W. Bartsch, Samantha L. Burton, Hannah B. Gold, Anatoliy Bushnev, Cynthia A. Derdeyn, Adriaan E. Basson, Dennis C. Liotta, and Eric J. Miller

Subjects
prodrugs, HIV, tenofovir, metabolism, lipids, nucleoside, Therapeutics. Pharmacology, RM1-950
Abstract

Nucleoside- and nucleotide-based therapeutics are indispensable treatment options for patients suffering from malignant and viral diseases. These agents are most commonly administered to patients as prodrugs to maximize bioavailability and efficacy. While the literature provides a practical prodrug playbook to facilitate the delivery of nucleoside and nucleotide therapeutics, small context-dependent amendments to these popular prodrug strategies can drive dramatic improvements in pharmacokinetic (PK) profiles. Herein we offer a brief overview of current prodrug strategies, as well as a case study involving the fine-tuning of lipid prodrugs of acyclic nucleoside phosphonate tenofovir (TFV), an approved nucleotide HIV reverse transcriptase inhibitor (NtRTI) and the cornerstone of combination antiretroviral therapy (cART). Installation of novel lipid terminal motifs significantly reduced fatty acid hepatic ω-oxidation while maintaining potent antiviral activity. This work contributes important insights to the expanding repertoire of lipid prodrug strategies in general, but particularly for the delivery and distribution of acyclic nucleoside phosphonates.

Published
2023
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2. ω-Functionalized Lipid Prodrugs of HIV NtRTI Tenofovir with Enhanced Pharmacokinetic Properties

Author

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, and Cynthia A. Derdeyn

Subjects
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
Abstract

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.

Published
2021
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