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

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 t 1/2 values than TXL in human liver microsomes, potent anti-HIV activity in vitro, and enhanced pharmacokinetic properties in vivo.

Prodrugs of a 1-Hydroxy-2-oxopiperidin-3-yl Phosphonate Enolase Inhibitor for the Treatment of ENO1-Deleted Cancers

“…These included a lipid prodrug 28 , a bis-cyanoethyl prodrug 29 , and salicylic alcohol (“cycloSal”) 30 prodrugs (Table , entries 19–21). The proposed mechanisms of action for these prodrugs are as follows: phospholipase and alkalinity. − Lipid prodrug 28 was synthesized by N , N ′-dicyclohexylcarbodiimide coupling between intermediate 7 and 3-(hexadecyloxy)­propan-1-ol, followed by the palladium-catalyzed hydrogenation of the product precursor. Lipid prodrug 28 was obtained as an off-white waxy solid in 36% yield.…”

Regioselective Ni-Catalyzed reductive alkylsilylation of acrylonitrile with unactivated alkyl bromides and chlorosilanes

“…Organosilicon compounds have continuously received more and more attentions over the past decades because of their unique properties and broad applications in a variety of areas. For instance, as a bioisostere of carbon atom in medicine 1 – 5 , silicon has different physical and electronic properties in a number of aspects, which result in low toxicity, increased lipophilicity, significantly tuned polarization and favorable metabolic profiles compared with its carbon analogue. On the other hand, silicon-containing molecules have impressive applications in advanced hybrid materials 6 – 8 and surface modification 9 – 11 .…”

An O-Benzyl Phosphonamidate Prodrug of Tenofovir for the Treatment of Hepatitis B Virus Infection

“…To address this issue, the two FDA-approved antiviral drugs, tenofovir disoproxil fumarate (TDF) and tenofovir alafenamide fumarate (TAF) (Figure ), were designed as prodrugs of the parent compound by covering the phosphonic acid moiety. In addition, recently several new prodrug forms − of tenofovir have also been reported as antiviral agents against HBV or HIV infection.…”