Synthesis and Evaluation of 2-Pyridinone Derivatives as HIV-1-Specific Reverse Transcriptase Inhibitors. 2. Analogues of 3-Aminopyridin-2(1H)-one

Walfred S. Saari, John S. Wai, Thorsten E. Fisher, Craig M. Thomas, Jacob M. Hoffman, Clarence S. Rooney, Anthony M. Smith, James H. Jones, Dona L. Bamberger, Mark E. Goldman, Julie A. O'Brien, Jack H. Nunberg, Julio C. Quintero, William A. Schleif, Emilio A. Emini, Paul S. Anderson

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Abstract

A series of nonnucleoside 3-aminopyridin-2(1H)-one derivatives was synthesized and evaluated for HIV-1 RT inhibitory properties. Several analogs proved to be potent and highly selective antagonists with in vitro IC50 values as low as 19 nM in the enzyme assay using rC-dG as template-primer. Two compounds from this series, 3-[[(4,7-dimethylbenzoxazol-2-yl)methyl]-amino]-5-ethyl-6-methylpyridin-2(1H)-one (34, L-697,639) and the corresponding 4,7-dichloro analogue (37, L-697,661) inhibited the spread of HIV-1 IIIb infection by 95% in MT4 cell culture at concentrations of 25-50 nM and were selected for clinical trials as antiviral agents.

Original languageEnglish
Pages (from-to)3792-3802
Number of pages11
JournalJournal of Medicinal Chemistry
Volume35
Issue number21
DOIs
StatePublished - Oct 1 1992

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