Background:  HIV-1 Integrase inhibitors (INI) have become one of the most promising classes of antiretrovirals. The advent of INI has given rise to extensive discovery programs; however, significant room for improvement in dose, dosing interval, potency against resistant mutations, and barrier to resistance remain.

Methods:  A rational design approach based on a 2-metal binding pharmacophore model was used to build potent inhibitors against recombinant HIV-1 integrase. Antiviral activity in single and multi-round assays was measured along with key INI-resistant mutants early in the compound triage strategy. Activity in combination with approved HIV drugs and across broad subtypes was measured. In addition, protein adjusted antiviral activity was measured to estimate efficacious C_MIN drug concentrations. Pharmacokinetic properties in multiple species were collected to find the most robust coverage of targeted C_MIN at 24 hours post dosing.

Results:  Optimization of a series of tricyclic hydroxy-pyridone carboxamides led to the discovery of S/GSK1349572. S/GSK134957 displays potent antiviral activity to wild type (wt) (0.15 ng/mL, PBMC) and key INI-resistant mutants (fold change 1.37X vs. N155H, 3.75X vs. G140S/Q148H). S/GSK134957 was additive or synergistic with no observed antagonism of antiviral activity with approved drugs from all classes. Sub nM IC50s were determined broadly against multiple HIV-1 subtypes and HIV-2 isolates in peripheral blood mononuclear cells. The preclinical pharmacokinetic profile predicted once daily dosing from high in vitro hepatocyte stability (rat & human, t_1/2 >360 min), low in vivo clearance, and good oral bioavailability, Cl (%F), across species, (rat 0.2 mL/min/kg (35%), dog 2.2 (35%), cyno 2.1 (25%)). The protein adjusted IC₉₀ of 64 ng/mL (wt) for S/GSK134957 was determined in preclinical species, and allometric scaling predicted a human t_1/2 enabling once daily dosing without a need for pharmacologic boosting agents. These preclinical attributes were borne out in a phase 2a clinical study wherein S/GSK134957 50 mg QD for 10 days produced a 2.5 log10 copies/mL reduction in HIV RNA.

Conclusions:  By analyzing structural alterations on both the activity against key integrase substitutions and PK parameters across multiple species, we have identified a potent series of HIV-1 integrase inhibitors. S/GSK134957, which has the potential to treat wt and INI resistant mutants with a low once daily dose, is the lead clinical candidate.