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.
Since the discovery of HIV as the etiological agent of AIDS, the virus has infected millions of people each year. Fortunately, with the use of HAART, viremia can be suppressed to below detectable levels in the infected individuals, which significantly improves their quality of life and prevents the onset of AIDS. However, HAART is not curative and issues relating to adherence and drug resistance may lead to the re-emergence of viremia, the development of AIDS, and ultimately death. To address a pressing need for the development of new and efficacious antiretroviral agents with activity against viruses bearing prevalent resistant mutations, we have designed two generations of benzimidazolone derivatives as HIV non-nucleoside reverse transcriptase inhibitors. The first generation benzimidazolone inhibitors were found to be potent inhibitors of wild-type HIV reverse transcriptase but were ineffective in the presence of common resistance mutations such as K103N and Y181C. A second generation benzimidazolone inhibitor (compound 42) not only showed inhibitory activity against wild-type HIV but also remained active against HIV containing the K103N, Y181C, and K103N/Y181C drug resistance mutations.
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