Discovery of 2‑Pyridinone Aminals: A Prodrug Strategy to Advance a Second Generation of HIV‑1 Integrase Strand Transfer Inhibitors

The search for new molecular constructs
that resemble the critical
two-metal binding pharmacophore required for HIV integrase strand
transfer inhibition represents a vibrant area of research within drug
discovery. Here we present the discovery of a new class of HIV integrase
strand transfer inhibitors based on the 2-pyridinone core of MK-0536.
These efforts led to the identification of 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 with limited oral absorption
and required an innovative prodrug strategy to enhance the high-dose
plasma exposures of the parent molecules.