Evolving structure-activity studies using an azabicyclic carbamoyl pyridone series resulted several leads with promising antiviral properties. Potency against a panel of clinically relevant resistant mutants derived from first generation HIV integrase inhibitor experience (raltegravir and elvitegravir) and drug concentration at 24 hours after dosing (C24) were key criteria in our evaluation.  These favorable antiviral data along data suggestive of a lack of cross-resistance to existing agents and a pharmacokinetic profile predictive of once daily (qd) dosing without pk boosting agents resulted in the selection of Shionogi/GSK1362867 as a pre-clinical candidate. The lead optimization and selection strategy to balance antiviral, pharmacokinetic and physicochemical properties used for the discovery and pre-clinical data of Shionogi/GSK1362867 will be the subject of this presentation.  This work has led to a suitable back-up to the late stage clinical asset dolutegravir.

Discovery of novel HIV integrase inhibitors part 2:  Selection and evaluation of an azabicyclic carbamoyl pyridone inhibitor as a pre–clinical candidate

245th National Meeting (2013)

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