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Discovery and Development of 2-Pyridinone HIV-1 Reverse Transcriptase Inhibitors

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The Search for Antiviral Drugs

Abstract

Merck’s commitment to the development of antivirals and vaccines for the treatment/prevention of human immunodeficiency virus (HIV) infection began in 1986 with the formation of an AIDS Task Force. This committee examined the HIV replication cycle to determine which targets had the greatest potential to be exploited for therapeutic intervention. Teams were then formed around each target to develop a better understanding of their biology as well as to devise screening assays for identification of leads. This mechanism-based approach toward drug development was chosen over a cell culture screening approach for many reasons. First, by understanding the molecular aspects of a target, novel sites for inhibition may become evident. Second, excellent inhibitors may be missed in a cell culture assay owing to irrelevant chemical properties (i.e., chemical instability of a compound during incubation, or inability of a compound to cross the cell membrane). Finally, the cell culture screening approach was not used in an effort to reduce the chance exposure of lab personnel to HIV infection.

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References

  • Byrn SR, Carlson DV, Chen JK, Cushman MS, Goldman ME, Ma WP, Pidgeon CL, Ray, KA, Stowell JG, Weith HL (1991): Drug-oligonucleotide conjugates. Adv Drug Delivery Rev 6:287–308.

    Article  Google Scholar 

  • Chang RSL, Lotti VJ, Monaghan, RL, Birnbaum J, Stapley, EO, Goetz MA, Albers-Schonberg G, Patchett AA, Liesch JM, Hensens, OD, Springer JP (1985): A potent nonpeptide cholecystokinin antagonist selective for peripheral tissues isolated from Aspergillus alliadus. Science 230:177–179.

    Article  Google Scholar 

  • Davey, R Jr, Laskin O, Decker M, O’Neill D, Haneiwich S, Metcalf J, Polis M, Kovacs J, Davis S, Mauer M, Yoder C, Patterson P, Justice S, Yeh KC, Woolf E, Au T, Lane HC (1991): L-697,639 and L-697,661: Novel agents for treatment of human immunodeficiency virus type 1 infection. 31st Intersci Conf Antimicrob Agents Chemother., Abstr 697.

    Google Scholar 

  • Folks TM, Powell D, Lightfoote M, Koenig S, Fauci A, Benn S, Rabson A, Dagherty D, Gendelman HE, Hoggan MD, Venkatesan S, Martin MA (1986): Biological and biochemical characterization of a cloned leu-3-cell surviving infection with the AIDS virus. J Exp Med 164:280–290.

    Article  Google Scholar 

  • Goldman ME (1991a): Molecular strategies for the inhibition of human immunodeficiency virus reverse transcriptase. Am J Pharm Educ 55:387–390.

    Google Scholar 

  • Goldman ME (1991b): L-697,661. AIDS Clin Trial Groups Primary Infect Comm Meet, Washington DC, 1991.

    Google Scholar 

  • Goldman ME, Salituro GS, Bowen JA, Williamson JM, Zink DL, Schleif WA, Emini EA (1990): Inhibition of human immunodeficiency virus-1 reverse transcriptase activity by rubromycins: Competitive interaction at the template ·primer site. Mol Pharmacol 38:20–25.

    Google Scholar 

  • Goldman ME, Nunberg JH, O’Brien JA, Quintero JC, Schleif WA, Freund KF, Gaul SL, Saari WS, Wai JS, Hoffman JM, Anderson PS, Hupe DJ, Emini EA, Stern AM (1991): Pyridinone derivatives: Specific human immunodeficiency virus type 1 reverse transcriptase inhibitors with antiviral activity. Proc Natl Acad Sci USA 88:6863–6867.

    Article  Google Scholar 

  • Goldman ME, O’Brien JA, Ruffing TL, Nunberg JH, Schleif WA, Quintero JC, Siegl PKS, Hoffman JM, Smith AM, Emini EA (1992): L-696,229 specifically inhibits HIV-1 reverse transcriptase and possesses antiviral activity, in vitro. Antimicrob Agents Chemother 36:1019–1023.

    Article  Google Scholar 

  • Halpin RA, Geer LA, Wyatt DW, Vyas KP, Hichens MP (1992): The disposition of L-696,229, a potent and specific inhibitor of human immunodeficiency virus reverse transcriptase in rats and Rhesus monkeys. FASEB J., in press.

    Google Scholar 

  • Hoffman JM, Wai JS, Thomas CM, Levin RB, O’Brien JA, Goldman, ME (1992): Synthesis and evaluation of 2-pyridone derivatives as HIV-1 specific reverse transcriptase inhibitors. 1. Phthalimidoalkyl and-alkylamino analogues. J Med Chem 35:3784–3791.

    Article  Google Scholar 

  • Kohl NE, Emini EA, Schleif WA, Davis LJ, Heimbach JC, Dixon RAF, Scolnick EM, Sigal IS (1988): Active human immunodeficiency virus protease is required for viral infectivity. Proc Natl Acad Sci USA 85:4696–4690.

    Article  Google Scholar 

  • Larder BA, Purifoy DJM, Powell KL, Darby G (1987): Site-specific mutagenesis of AIDS virus reverse transcriptase. Nature (London) 327:716–717.

    Article  Google Scholar 

  • Larder BA, Darby G, Richman DD (1989): HIV with reduced sensitivity to zidovudine (AZT) isolated during prolonged therapy. Science 243:1731–1734.

    Article  Google Scholar 

  • Laskin, OL, Dupont AG, Buntinx A, Schoors D, De Pré M, Van Hecken, A, Yeh KC, Woolf E, Eisenhandler R, De Smet M, Patterson P, De Lepeleire I, De Schepper PJ (1991): Human pharmacokinetics and tolerability of L-697,661 and L-697,639: Nonnucleoside human immunodeficiency virus type 1 reverse transcriptase inhibitors. 31st Intersci Conf Antimicrob Agents Chemother, Abstr 698.

    Google Scholar 

  • Merluzzi VJ, Hargrave KD, Labadia M, Grozinger K, Skoog M, Wu JC, Shih K-C, Eckner K, Hattox S, Adams J, Rosenthal AS, Faanes R, Eckner RJ, Koup RA, Sullivan JL (1990): Inhibition of HIV-1 replication by a nonnucleoside reverse transcriptase inhibitor. Science 250:1411–1413.

    Article  Google Scholar 

  • Mitsuya H, Weinhold KJ, Furman PJ, St Clair MH, Lehrman SN, Gallo RC, Bolognesi D, Barry DW, Broder S (1985): 3′-Azido-3′-deoxythymidine (BW A509U): An antiviral agent that inhibits the infectivity and cytopathic effect of human T-lymphotropic virus type III/lymphadenopathy-associated virus in vitro. Proc Natl Acad Sci USA 82:7096–7100.

    Article  Google Scholar 

  • Navia MA, Fitzgerald PMD, McKeever BM, Leu C-T, Heimbach JC, Herber WK, Sigal IS, Darke PL, Springer JP (1989): Three dimensional structure of aspartyl protease from human immunodeficiency virus HIV-1. Nature (London) 337:615–620.

    Article  Google Scholar 

  • Nunberg JH, Schleif WA, Boots EJ, O’Brien JA, Quintero JC, Hoffman JM, Emini EA, Goldman ME (1991): Viral resistance to human immunodeficiency virus type 1-specific pyridinone reverse transcriptase inhibitors. J Virol 65:4887–4892.

    Google Scholar 

  • Oberg B (1989): Antiviral effects of phosphonoformate (PFA, Foscarnet sodium). Pharmacol Ther 40:213–285.

    Article  Google Scholar 

  • O’Brien JA, Ostovic D, Schorn TW, Smith SJ, Ruffing TL, Siegl PKS, Goldman ME (1992): A rapid bioassay for the determination of non-nucleoside HIV-1 reverse transcriptase inhibitor plasma levels. Life Sci 52:243–249.

    Article  Google Scholar 

  • Pauwels R, Andries K, Desmyter J, Schols D, Kukla MJ, Breslin HJ, Raeymaeckers A, Van Gelder J, Woestenborghs R, Heykants J, Schellenkens K, Janssen MAC, De Clercq E, Janssen PAJ (1990): Potent and selective inhibition of HIV-1 replication in vitro by a novel series of TIBO derivatives. Nature (London) 343:470–474.

    Article  Google Scholar 

  • Pettibone DJ, Clineschmidt BV, Anderson PS, Freidinger RM, Lundell GF, Koupal LR, Schwartz CD, Williamson JM, Goetz MA, Hensens OD, Liesch JM, Springer JP (1989): A structurally unique, potent and selective oxytocin antagonist derived from Streptomyces silvensis. Endocrinology (Baltimore) 125:217–222.

    Article  Google Scholar 

  • Saari WS, Hoffman JM, Wai JS, Fisher TE, Rooney CS, Smith AM, Thomas CM, Goldman ME, O’Brien JA, Nunberg JH, Quintero JC, Schleif WA, Emini EA, Stern AM, Anderson PA (1991): 2-Pyridinone derivatives: A new class of nonnucleoside, HIV-1-specific reverse transcriptase inhibitors. J Med Chem 34:2922–2925.

    Article  Google Scholar 

  • Saari WS, Wai JS, Fisher TE, Thomas CM, Hoffman JM, Rooney CS, Smith AM, Jones JH, Bamberger DL, Goldman ME, O’Brien JA, Nunberg JH, Quintero JC, Schleif WA, Emini EA, Anderson PS (1992): Synthesis and evaluation of 2-pyridinone derivatives as HIV-1-specific reverse transcriptase inhibitors. 2. Analogues of 3-aminopyridin-2(1H)-one. J Med Chem 35:3792–3802.

    Article  Google Scholar 

  • Spadari S, Sala F, Pedrali-Noy G (1982): Aphidicolin: A specific inhibitor of nuclear DNA replication in eukaryotes. Trends Biochem Sci 7:29–32.

    Article  Google Scholar 

  • White EL, Buckheit RW Jr, Ross LJ, Germany JM, Andries K, Pauwels R, Janssen PAJ, Shannon WM, Chirigos MA (1991): A TIBO derivative, R82913, is a potent inhibitor of HIV-1 reverse transcriptase with heteropolymeric templates. Antiviral Res 16:257–266.

    Article  Google Scholar 

  • Wieland T, Gotzendorfer C, Zanotti G, Vaisius AC (1981): The effect of the chemical nature of the side chains of amatoxins in the inhibition of eukaryotic RNA polymerase B. Eur J Biochem 117:161–164.

    Article  Google Scholar 

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Authors
  1. Mark E. Goldman
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Editors and Affiliations

  1. Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, P.O. Box 368, Ridgefield, CT, 06877-0368, USA

    Julian Adams  & Vincent J. Merluzzi  & 

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© 1993 Springer Science+Business Media New York

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Goldman, M.E. (1993). Discovery and Development of 2-Pyridinone HIV-1 Reverse Transcriptase Inhibitors. In: Adams, J., Merluzzi, V.J. (eds) The Search for Antiviral Drugs. Birkhäuser, Boston, MA. https://doi.org/10.1007/978-1-4899-6718-3_5

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  • DOI: https://doi.org/10.1007/978-1-4899-6718-3_5

  • Publisher Name: Birkhäuser, Boston, MA

  • Print ISBN: 978-1-4899-6720-6

  • Online ISBN: 978-1-4899-6718-3

  • eBook Packages: Springer Book Archive

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