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Building Metabolically Stable and Potent Anti-HIV Thioether-Lipid Analogues of Tenofovir Exalidex: A thorough Pharmacological Analysis. | LitMetric

AI Article Synopsis

  • Tenofovir (TFV) is a prodrug used to treat HIV but suffers from poor bioavailability and toxicity due to early metabolism.
  • Researchers have developed new analogs of TFV, specifically the lipid-conjugated TFV exalidex (TXL) and its derivative, the hexadecylthiopropyl (HTP), which show better stability and activity.
  • Despite the promising results in animal studies, there is a need for additional optimization to align in vitro findings with in vivo pharmacokinetics for ongoing development.

Article Abstract

Inherently limited by poor bioavailability, antiviral agent tenofovir (TFV) is administered to people living with HIV in prodrug form. However, current prodrugs are prematurely metabolized, compromising access to HIV-infected cells and inducing toxicity. Inspired by lipid conjugate TFV exalidex (TXL), we recently disclosed TXL analogs with potent activity and robust hepatic stability in vitro, as well as attractive oral PK profiles in vivo. In parallel, we discovered the equipotent and equally stable hexadecylthiopropyl (HTP) derivative of TXL (). Reported herein are the synthetic and bioanalytic efforts that led to potent, safe, and hepatically stable HTP derivatives. While HTP analog showed the most attractive PK profile in mice (55% F) discrepancies in translating in vitro cell-based results to in vivo PK data, for certain prodrugs, indicated that further in vitro/in vivo optimization is required for continued advancement of this program.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11513920PMC
http://dx.doi.org/10.1021/acs.jmedchem.4c01510DOI Listing

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