16th International HIV Drug Resistance Workshop 12-16 June 2007, Barbados

α-SUBSTITUTED ACETANILIDES: HIV-1 NNRTIS WITH IMPROVED ACTIVITY AGAINST NNRTI-RESISTANT VIRUSES

Antivir Ther. 2007; 12:S31 (abstract no. 29)

MD Miller for the NNRTI Discovery Team
Merck Research Laboratories, West Point, PA, USA

Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are a mainstay of first-line regimens for treating HIV-1 infection. However, there is a need for new NNRTIs to address the increasing prevalence of NNRTI resistance and for sequencing in later lines of therapy. We describe here our progress toward identifying next-generation NNRTIs with good antiviral potency against many common NNRTI-resistant variants.

Using a high-throughput screening approach, we identified tetrazole thioacetanilides as a new structural class of potent NNRTIs that retained potency against the K103N RT mutant but exhibited reduced activity with other common NNRTI mutations (Muraglia et al. Bioorg Med Chem Lett. 2006 May 15;16(10):2748-52). From these early leads we evolved novel templates, generically known as α-substituted acetanilides, that display improved resistance properties. We have explored the structural basis for the activity of these compounds relative to NNRTI resistance by generating co-crystal structures with HIV-1 RT. Compound 2 is equipotent against wild-type and K103N viruses, but loses ~14-fold potency against the Y181C virus. The X-ray cocrystal structure shows that compound 2 makes a hydrogen bond with the main-chain nitrogen of K103, possibly explaining why it retains good potency against K103N. The structure also shows that Y181 is flipped out of the NNRTI binding site; replacement with cysteine may create the possibility for steric clash with the compound. In addition, broader resistance profiling showed that compound 2 lost significant activity against other clinically relevant mutants (e.g. G190S, ~50-fold resistance).

Compound 3 is essentially equipotent against wild-type, K103N, and Y181C viruses. Furthermore, compound 3 had a fold-change IC₅₀ of <sixfold against 12 of 16 isolates with clinically relevant NNRTI resistance mutations (five single mutants, and seven double or triple mutants). Mutants with >sixfold resistance included K103N/Y181C (20-fold), K103N/Y181C/G190A (14-fold), V106A/G190A/F227L (350-fold), and Y188L (390-fold).

The new structural classes of NNRTIs presented here include compounds with excellent antiviral potency against wild-type viruses as well as K103N, Y181C, and many other common NNRTI-resistant mutants. In addition, some of these compounds display good pharmacokinetic properties, suggesting this novel template may provide a source of new NNRTI candidates for clinical development.

2007-06-12
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