The discovery of S/GSK1265744: a carbamoyl pyridone HIV-1 integrase inhibitor

Background : HIV-1 integrase is a virally encoded enzyme essential for lentiviral replication. Assiduous medicinal chemistry efforts culminated in the discovery of raltegravir, the first marketed HIV-1 integrase inhibitor (INI). However, there is significant opportunity for improvement including overall dose burden, dosing interval and potency against resistant viruses. Our molecular design approach used a two-metal binding pharmacophore strategy and succeeded in identification of carbamoyl pyridone HIV-1 INIs. This enriched core scaffold has abundant structural features expanding the opportunity to control drug properties, leading to the discovery of S/GSK1265744. Methods : The carbamoyl pyridone scaffold was derivatized and evaluated for antiviral activity against wild-type virus (±HSA) along with key INI-resistant mutants. Animal pharmacokinetic profiles including a key measure of the trough drug concentration over protein-adjusted antiviral potency (C24/PAIC 50 ) along with in vitro DMPK properties, were used along with the virological data for compound selection. Results :The carbamoyl pyridone series inhibitors exhibited potent antiviral profiles with promising DMPK properties. S/GSK1265744 demonstrated good coverage of C24 over PAIC 50 predicting low mg unboosted once daily dosing, now validated in phase 2 clinical studies. These preclinical data along with a long human T 1/2 of ~30 hours in oral tablet study supports S/GSK1265744 as a long acting parenteral agent for once-monthly or less frequent dosing. Conclusions : A medicinal chemistry approach utilizing key viral mutants in combination with C24/PAIC 50 has allowed for discovery of S/GSK1265744. This agent is currently in phase 2 development evaluating a novel, long-acting parenteral route of administration and may enable new approaches to HIV therapy and prevention. (Published: 11 November 2012) Citation: Abstracts of the Eleventh International Congress on Drug Therapy in HIV Infection Taoda Y et al. Journal of the International AIDS Society 2012, 15 (Suppl 4):18267 http://www.jiasociety.org/index.php/jias/article/view/18267 | http://dx.doi.org/10.7448/IAS.15.6.18267