Background:  New nonnucleoside reverse transcriptase inhibitor (NNRTI)-class compounds that provide more durable suppression of HIV replication with improved tolerability could prove clinically useful. Efficacy against wild type and mutant strains, an increased barrier to the development of resistance, and favorable pharmacokinetics are essential attributes. IDX12899 and IDX12989 are novel phospho-heterocyclic NNRTI with the potential to fit such a profile.

Methods:  Enzyme and cell-based assays were conducted on a spectrum of wild type HIV-1 subtypes and on a panel of strains with various single and multiple NNRTI resistance mutations. Studies included barrier to resistance development and selection of in vitro resistance by phenotypic and genotypic analyses. X-ray crystallography established the 3-D structures of the IDX compounds complexed with HIV-1 reverse transcriptase containing double (Y181C/K103N) NNRTI resistance mutations. Oral absorption, metabolism, and pharmacokinetics were studied in the rat, rabbit, dog, and monkey. Metabolic stability was assessed in human hepatic microsomes and primary hepatocytes. GLP toxicology studies were conducted to support a human micro-dose study using ¹⁴C-labeled compounds and accelerator mass spectroscopy. CNS safety pharmacology and the standard battery of genotoxicity studies were conducted.

Results:  Both IDX compounds show nM to sub-nM activity against a broad panel of subtype B and non-B wild type HIV-1 isolates, with 50% cellular cytotoxicity observed at 15 to 70 mM. Potency is retained against panels of clinical isolates containing various single and double NNRTI mutations, including those associated with high-level resistance to efavirenz. Barrier to resistance studies in vitro show the IDX compounds to be superior to efavirenz. For both IDX compounds, oral absorption in the monkey was around 60% and plasma drug levels significantly exceeded EC₉₀ values 24 hours post-dose. No adverse effects were observed in acute toxicity studies in rats and monkeys administered up to 1000 mg/kg. Genotoxicity studies were negative. Both IDX compounds are weak to moderate inducers of CYP450 3A4.

Conclusions:  The IDX NNRTI are potent inhibitors of wild type and resistant HIV-1 and demonstrate superior barriers to resistance development compared to efavirenz.  Extrapolation from animal data supports the potential for once-daily dosing in humans.