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Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1991 Aug 1;88(15):6863–6867. doi: 10.1073/pnas.88.15.6863

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

M E Goldman 1, J H Nunberg 1, J A O'Brien 1, J C Quintero 1, W A Schleif 1, K F Freund 1, S L Gaul 1, W S Saari 1, J S Wai 1, J M Hoffman 1, et al.
PMCID: PMC52189  PMID: 1713693

Abstract

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.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Butler K. M., Husson R. N., Balis F. M., Brouwers P., Eddy J., el-Amin D., Gress J., Hawkins M., Jarosinski P., Moss H. Dideoxyinosine in children with symptomatic human immunodeficiency virus infection. N Engl J Med. 1991 Jan 17;324(3):137–144. doi: 10.1056/NEJM199101173240301. [DOI] [PubMed] [Google Scholar]
  2. Cha S. Tight-binding inhibitors-I. Kinetic behavior. Biochem Pharmacol. 1975 Dec 1;24(23):2177–2185. doi: 10.1016/0006-2952(75)90050-7. [DOI] [PubMed] [Google Scholar]
  3. Chang L. M., Rafter E., Augl C., Bollum F. J. Purification of a DNA polymerase-DNA primase complex from calf thymus glands. J Biol Chem. 1984 Dec 10;259(23):14679–14687. [PubMed] [Google Scholar]
  4. Debyser Z., Pauwels R., Andries K., Desmyter J., Kukla M., Janssen P. A., De Clercq E. An antiviral target on reverse transcriptase of human immunodeficiency virus type 1 revealed by tetrahydroimidazo-[4,5,1-jk] [1,4]benzodiazepin-2 (1H)-one and -thione derivatives. Proc Natl Acad Sci U S A. 1991 Feb 15;88(4):1451–1455. doi: 10.1073/pnas.88.4.1451. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. ELION G. B., SINGER S., HITCHINGS G. H. Antagonists of nucleic acid derivatives. VIII. Synergism in combinations of biochemically related antimetabolites. J Biol Chem. 1954 Jun;208(2):477–488. [PubMed] [Google Scholar]
  6. FOLEY G. E., LAZARUS H., FARBER S., UZMAN B. G., BOONE B. A., MCCARTHY R. E. CONTINUOUS CULTURE OF HUMAN LYMPHOBLASTS FROM PERIPHERAL BLOOD OF A CHILD WITH ACUTE LEUKEMIA. Cancer. 1965 Apr;18:522–529. doi: 10.1002/1097-0142(196504)18:4<522::aid-cncr2820180418>3.0.co;2-j. [DOI] [PubMed] [Google Scholar]
  7. Fischl M. A., Richman D. D., Grieco M. H., Gottlieb M. S., Volberding P. A., Laskin O. L., Leedom J. M., Groopman J. E., Mildvan D., Schooley R. T. The efficacy of azidothymidine (AZT) in the treatment of patients with AIDS and AIDS-related complex. A double-blind, placebo-controlled trial. N Engl J Med. 1987 Jul 23;317(4):185–191. doi: 10.1056/NEJM198707233170401. [DOI] [PubMed] [Google Scholar]
  8. Gallo R. C., Salahuddin S. Z., Popovic M., Shearer G. M., Kaplan M., Haynes B. F., Palker T. J., Redfield R., Oleske J., Safai B. Frequent detection and isolation of cytopathic retroviruses (HTLV-III) from patients with AIDS and at risk for AIDS. Science. 1984 May 4;224(4648):500–503. doi: 10.1126/science.6200936. [DOI] [PubMed] [Google Scholar]
  9. Goff S., Traktman P., Baltimore D. Isolation and properties of Moloney murine leukemia virus mutants: use of a rapid assay for release of virion reverse transcriptase. J Virol. 1981 Apr;38(1):239–248. doi: 10.1128/jvi.38.1.239-248.1981. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Goldman M. E., Salituro G. S., Bowen J. A., Williamson J. M., Zink D. L., Schleif W. A., Emini E. A. Inhibition of human immunodeficiency virus-1 reverse transcriptase activity by rubromycins: competitive interaction at the template.primer site. Mol Pharmacol. 1990 Jul;38(1):20–25. [PubMed] [Google Scholar]
  11. Gurgo C., Guo H. G., Franchini G., Aldovini A., Collalti E., Farrell K., Wong-Staal F., Gallo R. C., Reitz M. S., Jr Envelope sequences of two new United States HIV-1 isolates. Virology. 1988 Jun;164(2):531–536. doi: 10.1016/0042-6822(88)90568-5. [DOI] [PubMed] [Google Scholar]
  12. Hahn B. H., Shaw G. M., Arya S. K., Popovic M., Gallo R. C., Wong-Staal F. Molecular cloning and characterization of the HTLV-III virus associated with AIDS. Nature. 1984 Nov 8;312(5990):166–169. doi: 10.1038/312166a0. [DOI] [PubMed] [Google Scholar]
  13. Hahn B. H., Shaw G. M., Taylor M. E., Redfield R. R., Markham P. D., Salahuddin S. Z., Wong-Staal F., Gallo R. C., Parks E. S., Parks W. P. Genetic variation in HTLV-III/LAV over time in patients with AIDS or at risk for AIDS. Science. 1986 Jun 20;232(4757):1548–1553. doi: 10.1126/science.3012778. [DOI] [PubMed] [Google Scholar]
  14. Herdewijn P., Balzarini J., De Clercq E., Pauwels R., Baba M., Broder S., Vanderhaeghe H. 3'-substituted 2',3'-dideoxynucleoside analogues as potential anti-HIV (HTLV-III/LAV) agents. J Med Chem. 1987 Aug;30(8):1270–1278. doi: 10.1021/jm00391a003. [DOI] [PubMed] [Google Scholar]
  15. Katzenstein D. A., Vujcic L. K., Latif A., Boulos R., Halsey N. A., Quinn T. C., Rastogi S. C., Quinnan G. V., Jr Human immunodeficiency virus neutralizing antibodies in sera from North Americans and Africans. J Acquir Immune Defic Syndr. 1990;3(8):810–816. [PubMed] [Google Scholar]
  16. Larder B. A., Darby G., Richman D. D. HIV with reduced sensitivity to zidovudine (AZT) isolated during prolonged therapy. Science. 1989 Mar 31;243(4899):1731–1734. doi: 10.1126/science.2467383. [DOI] [PubMed] [Google Scholar]
  17. Merluzzi V. J., Hargrave K. D., Labadia M., Grozinger K., Skoog M., Wu J. C., Shih C. K., Eckner K., Hattox S., Adams J. Inhibition of HIV-1 replication by a nonnucleoside reverse transcriptase inhibitor. Science. 1990 Dec 7;250(4986):1411–1413. doi: 10.1126/science.1701568. [DOI] [PubMed] [Google Scholar]
  18. Mitsuya H., Yarchoan R., Broder S. Molecular targets for AIDS therapy. Science. 1990 Sep 28;249(4976):1533–1544. doi: 10.1126/science.1699273. [DOI] [PubMed] [Google Scholar]
  19. Miyoshi I., Kubonishi I., Yoshimoto S., Akagi T., Ohtsuki Y., Shiraishi Y., Nagata K., Hinuma Y. Type C virus particles in a cord T-cell line derived by co-cultivating normal human cord leukocytes and human leukaemic T cells. Nature. 1981 Dec 24;294(5843):770–771. doi: 10.1038/294770a0. [DOI] [PubMed] [Google Scholar]
  20. Pauwels R., Andries K., Desmyter J., Schols D., Kukla M. J., Breslin H. J., Raeymaeckers A., Van Gelder J., Woestenborghs R., Heykants J. Potent and selective inhibition of HIV-1 replication in vitro by a novel series of TIBO derivatives. Nature. 1990 Feb 1;343(6257):470–474. doi: 10.1038/343470a0. [DOI] [PubMed] [Google Scholar]
  21. Popovic M., Sarngadharan M. G., Read E., Gallo R. C. Detection, isolation, and continuous production of cytopathic retroviruses (HTLV-III) from patients with AIDS and pre-AIDS. Science. 1984 May 4;224(4648):497–500. doi: 10.1126/science.6200935. [DOI] [PubMed] [Google Scholar]
  22. Starnes M. C., Cheng Y. C. Human immunodeficiency virus reverse transcriptase-associated RNase H activity. J Biol Chem. 1989 Apr 25;264(12):7073–7077. [PubMed] [Google Scholar]
  23. Yarchoan R., Broder S. Anti-retroviral therapy of AIDS and related disorders: general principles and specific development of dideoxynucleosides. Pharmacol Ther. 1989;40(3):329–348. doi: 10.1016/0163-7258(89)90083-1. [DOI] [PubMed] [Google Scholar]

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