Open AccessThe discovery of S/GSK1265744: a carbamoyl pyridone HIV‐1 integrase inhibitor
Author(s) -
Taoda Y,
Johns B,
Weatherhead J,
Temelkoff D,
Kawasuji T,
Yoshida H,
Taishi T,
Kiyama R,
Fuji M,
Murai H,
Yoshinaga T,
Sato A,
Fujiwara T
Publication year - 2012
Publication title -
journal of the international aids society
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.724
H-Index - 62
ISSN - 1758-2652
DOI - 10.7448/ias.15.6.18267
Subject(s) - pharmacophore , integrase , dolutegravir , integrase inhibitor , drug discovery , dosing , potency , pharmacology , pharmacokinetics , raltegravir , medicine , drug , virology , adme , human immunodeficiency virus (hiv) , in vitro , chemistry , biochemistry , viral load , antiretroviral therapy
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.