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

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.