Abstract
A series of nondimethylphenyl-diarylpyrimidines with much lower cytotoxicities than their dimethyl analogues were developed. Compound B13 with a difluorobiphenyl moiety showed the highest antiviral activity against WT, mutant strains, and RT. The hydrochloride form of B13 exhibited an improved water solubility of 5.6 μg/mL compared with ETR (≪1 μg/mL), better stability in human and rat liver microsomes, and a great oral bioavailability of 44%, making it promising as a drug candidate. In addition, no apparent toxicity was observed in the acute toxicity assay (2 g/kg) and HE staining.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Administration, Oral
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Animals
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Anti-HIV Agents / chemistry
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Anti-HIV Agents / pharmacokinetics
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Anti-HIV Agents / pharmacology*
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Apoptosis / drug effects*
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Drug Design*
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Female
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HIV Infections / drug therapy*
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HIV Infections / pathology
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HIV Infections / virology
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HIV-1 / drug effects
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HIV-1 / enzymology
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Humans
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Ligands
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Male
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Mice
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Microsomes, Liver / drug effects*
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Microsomes, Liver / metabolism
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Precursor Cell Lymphoblastic Leukemia-Lymphoma / drug therapy*
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Precursor Cell Lymphoblastic Leukemia-Lymphoma / pathology
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Precursor Cell Lymphoblastic Leukemia-Lymphoma / virology
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Rats
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Reverse Transcriptase Inhibitors / chemistry
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Reverse Transcriptase Inhibitors / pharmacokinetics
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Reverse Transcriptase Inhibitors / pharmacology*
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Tissue Distribution
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Tumor Cells, Cultured
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Virus Replication / drug effects
Substances
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Anti-HIV Agents
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Ligands
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Reverse Transcriptase Inhibitors