Pyridinone derivatives: Specific human immunodeficiency virus type 1 reverse transcriptase inhibitors with antiviral activity

Mark E. Goldman, Jack H. Nunberg, Julie A. O'Brien, Julio C. Quintero, William A. Schleif, Kurt F. Freund, S. Lee Gaul, Walfred S. Saari, John S. Wai, Jacob M. Hoffman, Paul S. Anderson, Donald J. Hupe, Emilio A. Emini, Andrew M. Stern

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331 Scopus citations


Derivatives of pyridinones were found to inhibit human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) activity and prevent the spread of HIV-1 infection in cell culture without an appreciable effect on other retroviral or cellular polymerases. 3-{[(4,7-Dimethyl-1,3-benzoxazol-2-yl)methyl]amino}-5-ethyl-6-methylpyridin- 2(1H)-one (L-697,639) and 3-{[(4,7-dichloro-1,3-benzoxazol-2-yl)methyl]amino}-5-ethyl-6-methylpyridin- 2(1H)-one (L-697,661), two compounds within this series, had HIV-1 RT IC50 values in the range of 20-800 nM, depending upon the template-primer used. The most potent inhibition was obtained with rC·dG and dA·dT as template-primers. With rC·dG, reversible slow-binding non-competitive inhibition was observed. [3H]L-697,639 bound preferentially to enzyme-template-primer complexes. This binding was magnesium-dependent and saturable with a stoichiometry of 1 mol of [3H]L-697,639 per mol of RT heterodimer. Displacement of [3H]L-697,639 was seen with phosphonoformate. In human T-lymphoid-cell culture, L-697,639 and L-697,661 inhibited the spread of HIV-1 infection by at least 95% at concentrations of 12-200 nM. Synergism between 3′-azido-3′-deoxythymidine or dideoxyinosine and either of these compounds was also demonstrated in cell culture. Based upon their specificity for HIV-1 RT activity, template-primer dependence on potency and ability to displace [3H]L-697,639; a tetrahydroimidazo[4,5,1-jk][1,4]-benzodiazepin-2(1H)-thione derivative R82150 and the dipyridodiazepinone BI-RG-587 appear to inhibit RT activity by the same mechanism as the pyridinones.

Original languageEnglish
Pages (from-to)6863-6867
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number15
StatePublished - Aug 1 1991


  • Acquired immunodeficiency syndrome
  • Antiviral agents
  • Inhibition kinetics
  • Synergy


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