| Autor: |
Pribut N; Department of Chemistry, Emory University, Atlanta, Georgia 30322, United States., D'Erasmo M; Department of Chemistry, Emory University, Atlanta, Georgia 30322, United States., Dasari M; Department of Chemistry, Emory University, Atlanta, Georgia 30322, United States., Giesler KE; Department of Chemistry, Emory University, Atlanta, Georgia 30322, United States., Iskandar S; Department of Chemistry, Emory University, Atlanta, Georgia 30322, United States., Sharma SK; Department of Chemistry, Emory University, Atlanta, Georgia 30322, United States., Bartsch PW; Department of Chemistry, Emory University, Atlanta, Georgia 30322, United States., Raghuram A; Department of Chemistry, Emory University, Atlanta, Georgia 30322, United States., Bushnev A; Department of Chemistry, Emory University, Atlanta, Georgia 30322, United States., Hwang SS; Department of Chemistry, Emory University, Atlanta, Georgia 30322, United States., Burton SL; Yerkes National Primate Research Center, Emory University, Atlanta, Georgia 30329, United States.; Emory Vaccine Center, Emory University, Atlanta, Georgia 30322, United States., Derdeyn CA; Yerkes National Primate Research Center, Emory University, Atlanta, Georgia 30329, United States.; Emory Vaccine Center, Emory University, Atlanta, Georgia 30322, United States.; Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia 30322, United States., Basson AE; HIV Pathogenesis Research Unit, Department of Molecular Medicine and Haematology, University of the Witwatersrand, Johannesburg, Gauteng 2193, South Africa., Liotta DC; Department of Chemistry, Emory University, Atlanta, Georgia 30322, United States., Miller EJ; Department of Chemistry, Emory University, Atlanta, Georgia 30322, United States. |
| Abstrakt: |
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 . |
