Abstract
In an effort to optimize the pharmacokinetic profile of GS-9160, a potent (EC50=1.2 – 4 nM) antiviral tri-cyclic HIV-1 integrase (IN) strand transfer inhibitor (INSTI), various substitutions on the p-fluorobenzyl moiety of GS-9160 were explored. This effort led to the discovery of GS-9224, an analog containing a 5-chloro-2,4-di-fluorobenzyl moiety. GS-9224, like its predecessor GS-9160, has potent (EC50=1.3 – 9 nM) and selective antiviral activity against HIV-1 and acts as a bona fide integration inhibitor through elevation of 2-long terminal repeat (2-LTR) circles and decrease of integration junctions in HIV-1 infected cells, markers of failed viral integration. Viral resistance selections with GS-9224 yielded three mutations within the catalytic core domain of HIV-1 IN: G140S, L74M and Q148K. When tested against a panel of HIV-1 clones engineered to express INSTI resistance mutations, the profile of GS-9224 was comparable to GS-9160. GS-9224 exhibits improved hepatic microsome stability, better absorption potential and a lower in vitro intestinal efflux ratio compared to GS-9160. In addition, GS-9224 displayed higher dog plasma protein binding (~99%) than GS-9160 (~93%) suggesting a potential for protein restricted clearance. However, the improved metabolic stability, absorption potential and serum protein binding of GS-9224 compared to GS-9160 did not translate into an improved clinical pharmacokinetic profile. Results from a single-dose study in human healthy subjects revealed a fast systemic clearance of GS-9224 with a terminal half-life of ~ 1 h, resulting in a pharmacokinetic profile that would not support once-daily dosing in HIV-infected patients.
Highlights
As an essential enzyme for HIV-1 replication, integrase (IN) is an attractive target for antiviral drug discovery
In an effort to improve the pharmacokinetic profile of previously published IN strand-transfer inhibitor (INSTI) GS-9160 [19,20,21], various substitutions on the p-fluorobenzyl moiety of GS-9160 were explored leading to the discovery of the close analog GS-9224 containing a 5-chloro-2,4fluorobenzyl moiety (Figure 1) [22]
To assess the impact of human serum protein binding on the antiviral potency of GS-9224 and to provide a target trough concentration in humans to achieve efficacy, the antiviral activity of GS-9224 was determined in the presence of human serum and the human serum components including human serum albumin (HSA)
Summary
As an essential enzyme for HIV-1 replication, integrase (IN) is an attractive target for antiviral drug discovery. Raltegravir (RAL) was the first IN strand-transfer inhibitor (INSTI) to be approved for clinical use and is dosed twice daily [3,4,5]. A once-daily single tablet regimen (STRIBILDTM) containing EVG, cobicistat, deoxyfluorothiacytidine (FTC) and tenofovir disoproxil fumarate (TDF) has been recently approved by the FDA for the treatment of HIV infection. The INSTI dolutegravir (S/GSK1349572), which is dosed once-daily without boosting, displayed a resistance profile that is distinct from those of RAL and EVG [16,17]. In phase III clinical studies, none of the subjects treated with the combination of dolutegravir and TDF/FTC for up to 48 weeks developed any treatment-associated IN mutations [18]. We describe detailed biological and metabolic characterization of GS-9224 including a clinical pharmacokinetic profile in healthy human volunteers
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