The search for new molecular constructs that resemble the critical 2-metal binding pharmacophore required for HIV integrase strand transfer inhibition represents a vibrant area of research within drug discovery.  Efforts are focused on the development of inhibitors that display broad resistance profiles and are amenable to once-daily or less frequent dosing.  Herein, we present our discovery efforts that led to the identification of a novel class of HIV integrase strand transfer inhibitors (InSTI) based on the 2-pyridinone core of MK-0536.  These efforts culminated in two lead compounds with excellent antiviral activity and preclinical pharmacokinetic profiles to support a once-daily human dose prediction.  Dose-escalating PK studies in dog revealed significant issues associated with limited oral absorption and required an innovative prodrug strategy to enhance high-dose plasma exposures of the parent molecules.  Our strategy relied on functionalizing two different accessible hydroxyl groups on the leading compounds to introduce promoieties, with prodrugs designed to independently address the limited aqueous solubility and limited permeability of the parent compounds.  From these efforts, a unique phosphate/carbonate acetal “double–prodrug” was identified from these efforts, which achieved high parent plasma exposures and provided a path to further advance this new class of InSTI.<br/>

Discovery of 2-pyridinone aminals: A prodrug strategy to advance a second generation of HIV-1 integrase strand transfer inhibitors

254th National Meeting (2017)

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