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

• Published in: Journal of medicinal chemistry Vol. 58; no. 20; pp. 8154 - 8165
• Main Authors: Raheem, Izzat T, Walji, Abbas M, Klein, Daniel, Sanders, John M, Powell, David A, Abeywickrema, Pravien, Barbe, Guillaume, Bennet, Amrith, Clas, Sophie−Dorothee, Dubost, David, Embrey, Mark, Grobler, Jay, Hafey, Michael J, Hartingh, Timothy J, Hazuda, Daria J, Miller, Michael D, Moore, Keith P, Pajkovic, Natasa, Patel, Sangita, Rada, Vanessa, Rearden, Paul, Schreier, John D, Sisko, John, Steele, Thomas G, Truchon, Jean-François, Wai, John, Xu, Min, Coleman, Paul J
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 22-10-2015; American Chemical Society (ACS)
• Subjects: 60 APPLIED LIFE SCIENCES; Animals; Area Under Curve; Dogs; Dose-Response Relationship, Drug; Drug Design; HIV Integrase - drug effects; HIV Integrase - metabolism; HIV Integrase Inhibitors - chemical synthesis; HIV Integrase Inhibitors - pharmacokinetics; HIV Integrase Inhibitors - pharmacology; HIV-1 - drug effects; HIV-1 - enzymology; HIV-1 - genetics; Humans; INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY; Models, Molecular; Prodrugs; Pyridones - chemical synthesis; Pyridones - pharmacokinetics; Pyridones - pharmacology; Rats
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.5b01037

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.