| Literature DB >> 26397965 |
Izzat T Raheem, Abbas M Walji, Daniel Klein, John M Sanders, David A Powell1, Pravien Abeywickrema, Guillaume Barbe1, Amrith Bennet, Karla Childers2, Melodie Christensen2, Sophie Dorothee Clas3, David Dubost, Mark Embrey, Jay Grobler, Michael J Hafey, Timothy J Hartingh, Daria J Hazuda, Jeffrey T Kuethe2, Jamie McCabe Dunn2, Michael D Miller, Keith P Moore, Andrew Nolting2, Natasa Pajkovic, Sangita Patel, Zuihui Peng2, Vanessa Rada, Paul Rearden, John D Schreier, John Sisko, Thomas G Steele, Jean-François Truchon1, John Wai, Min Xu, Paul J Coleman.
Abstract
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.Entities:
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Year: 2015 PMID： 26397965 DOI： 10.1021/acs.jmedchem.5b01037
Source DB: PubMed Journal: J Med Chem ISSN： 0022-2623 Impact factor: 7.446