2. Academic Validation
  3. ω-Functionalized Lipid Prodrugs of HIV NtRTI Tenofovir with Enhanced Pharmacokinetic Properties

ω-Functionalized Lipid Prodrugs of HIV NtRTI Tenofovir with Enhanced Pharmacokinetic Properties

  • J Med Chem. 2021 Sep 9;64(17):12917-12937. doi: 10.1021/acs.jmedchem.1c01083.
Nicole Pribut 1,  Michael D'Erasmo 1,  Madhuri Dasari 1,  Kyle E Giesler 1,  Sabrina Iskandar 1,  Savita K Sharma 1,  Perry W Bartsch 1,  Akshay Raghuram 1,  Anatoliy Bushnev 1,  Soyon S Hwang 1,  Samantha L Burton 2 3,  Cynthia A Derdeyn 2 3 4,  Adriaan E Basson 5,  Dennis C Liotta 1,  Eric J Miller 1
Affiliations

Affiliations

  • 1 Department of Chemistry, Emory University, Atlanta, Georgia 30322, United States.
  • 2 Yerkes National Primate Research Center, Emory University, Atlanta, Georgia 30329, United States.
  • 3 Emory Vaccine Center, Emory University, Atlanta, Georgia 30322, United States.
  • 4 Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia 30322, United States.
  • 5 HIV Pathogenesis Research Unit, Department of Molecular Medicine and Haematology, University of the Witwatersrand, Johannesburg, Gauteng 2193, South Africa.
PMID: 34459598 DOI: 10.1021/acs.jmedchem.1c01083
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.

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