• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information
Logo of aacPermissionsJournals.ASM.orgJournalAAC ArticleJournal InfoAuthorsReviewers
Antimicrob Agents Chemother. Dec 1995; 39(12): 2602–2605.
PMCID: PMC162996

L-743, 726 (DMP-266): a novel, highly potent nonnucleoside inhibitor of the human immunodeficiency virus type 1 reverse transcriptase.

Abstract

The clinical benefit of the human immunodeficiency virus type 1 (HIV-1) nonnucleoside reverse transcriptase (RT) inhibitors (NNRTIs) is limited by the rapid selection of inhibitor-resistant viral variants. However, it may be possible to enhance the clinical utility of this inhibitor class by deriving compounds that express both high levels of antiviral activity and an augmented pharmacokinetic profile. Accordingly, we developed a new class of NNRTIs, the 1, 4-dihydro-2H-3, 1-benzoxazin-2-ones. L-743, 726 (DMP-266), a member of this class, was chosen for clinical evaluation because of its in vitro properties. The compound was a potent inhibitor of the wild-type HIV-1 RT (Ki = 2.93 nM) and exhibited a 95% inhibitory concentration of 1.5 nM for the inhibition of HIV-1 replicative spread in cell culture. In addition, L-7743, 7726 was found to be capable of inhibiting, with 95% inhibitory concentrations of < or = 1.5 microM, a panel of NNRTI-resistant mutant viruses, each of which expressed a single RT amino acid substitution. Derivation of virus with notably reduced susceptibility to the inhibitor required prolonged cell culture selection and was mediated by a combination of at least two RT amino acid substitutions. Studies of L-743, 726 in rats, monkeys, and a chimpanzee demonstrated the compound's potential for good oral bioavailability and pharmacokinetics in humans.

Full Text

The Full Text of this article is available as a PDF (221K).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Althaus IW, Chou JJ, Gonzales AJ, Deibel MR, Chou KC, Kezdy FJ, Romero DL, Aristoff PA, Tarpley WG, Reusser F. Steady-state kinetic studies with the non-nucleoside HIV-1 reverse transcriptase inhibitor U-87201E. J Biol Chem. 1993 Mar 25;268(9):6119–6124. [PubMed]
  • Byrnes VW, Sardana VV, Schleif WA, Condra JH, Waterbury JA, Wolfgang JA, Long WJ, Schneider CL, Schlabach AJ, Wolanski BS, et al. Comprehensive mutant enzyme and viral variant assessment of human immunodeficiency virus type 1 reverse transcriptase resistance to nonnucleoside inhibitors. Antimicrob Agents Chemother. 1993 Aug;37(8):1576–1579. [PMC free article] [PubMed]
  • Carroll SS, Olsen DB, Bennett CD, Gotlib L, Graham DJ, Condra JH, Stern AM, Shafer JA, Kuo LC. Inhibition of HIV-1 reverse transcriptase by pyridinone derivatives. Potency, binding characteristics, and effect of template sequence. J Biol Chem. 1993 Jan 5;268(1):276–281. [PubMed]
  • Carroll SS, Stahlhut M, Geib J, Olsen DB. Inhibition of HIV-1 reverse transcriptase by a quinazolinone and comparison with inhibition by pyridinones. Differences in the rates of inhibitor binding and in synergistic inhibition with nucleoside analogs. J Biol Chem. 1994 Dec 23;269(51):32351–32357. [PubMed]
  • Dueweke TJ, Kézdy FJ, Waszak GA, Deibel MR, Jr, Tarpley WG. The binding of a novel bisheteroarylpiperazine mediates inhibition of human immunodeficiency virus type 1 reverse transcriptase. J Biol Chem. 1992 Jan 5;267(1):27–30. [PubMed]
  • Frank KB, Noll GJ, Connell EV, Sim IS. Kinetic interaction of human immunodeficiency virus type 1 reverse transcriptase with the antiviral tetrahydroimidazo[4,5,1-jk]-[1,4]-benzodiazepine-2-(1H)-thione compound, R82150. J Biol Chem. 1991 Aug 5;266(22):14232–14236. [PubMed]
  • Goldman ME, Nunberg JH, O'Brien JA, Quintero JC, Schleif WA, Freund KF, Gaul SL, Saari WS, Wai JS, Hoffman JM, et al. Pyridinone derivatives: specific human immunodeficiency virus type 1 reverse transcriptase inhibitors with antiviral activity. Proc Natl Acad Sci U S A. 1991 Aug 1;88(15):6863–6867. [PMC free article] [PubMed]
  • Kohlstaedt LA, Wang J, Friedman JM, Rice PA, Steitz TA. Crystal structure at 3.5 A resolution of HIV-1 reverse transcriptase complexed with an inhibitor. Science. 1992 Jun 26;256(5065):1783–1790. [PubMed]
  • Kopp EB, Miglietta JJ, Shrutkowski AG, Shih CK, Grob PM, Skoog MT. Steady state kinetics and inhibition of HIV-1 reverse transcriptase by a non-nucleoside dipyridodiazepinone, BI-RG-587, using a heteropolymeric template. Nucleic Acids Res. 1991 Jun 11;19(11):3035–3039. [PMC free article] [PubMed]
  • Nunberg JH, Schleif WA, Boots EJ, O'Brien JA, Quintero JC, Hoffman JM, Emini EA, Goldman ME. Viral resistance to human immunodeficiency virus type 1-specific pyridinone reverse transcriptase inhibitors. J Virol. 1991 Sep;65(9):4887–4892. [PMC free article] [PubMed]
  • Saag MS, Emini EA, Laskin OL, Douglas J, Lapidus WI, Schleif WA, Whitley RJ, Hildebrand C, Byrnes VW, Kappes JC, et al. A short-term clinical evaluation of L-697,661, a non-nucleoside inhibitor of HIV-1 reverse transcriptase. L-697,661 Working Group. N Engl J Med. 1993 Oct 7;329(15):1065–1072. [PubMed]
  • Saari WS, Wai JS, Fisher TE, Thomas CM, Hoffman JM, Rooney CS, Smith AM, Jones JH, Bamberger DL, Goldman ME, et al. 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. 1992 Oct 16;35(21):3792–3802. [PubMed]
  • Sardana VV, Emini EA, Gotlib L, Graham DJ, Lineberger DW, Long WJ, Schlabach AJ, Wolfgang JA, Condra JH. Functional analysis of HIV-1 reverse transcriptase amino acids involved in resistance to multiple nonnucleoside inhibitors. J Biol Chem. 1992 Sep 5;267(25):17526–17530. [PubMed]
  • Smerdon SJ, Jäger J, Wang J, Kohlstaedt LA, Chirino AJ, Friedman JM, Rice PA, Steitz TA. Structure of the binding site for nonnucleoside inhibitors of the reverse transcriptase of human immunodeficiency virus type 1. Proc Natl Acad Sci U S A. 1994 Apr 26;91(9):3911–3915. [PMC free article] [PubMed]
  • Spence RA, Kati WM, Anderson KS, Johnson KA. Mechanism of inhibition of HIV-1 reverse transcriptase by nonnucleoside inhibitors. Science. 1995 Feb 17;267(5200):988–993. [PubMed]
  • Stahlhut M, Li Y, Condra JH, Fu J, Gotlib L, Graham DJ, Olsen DB. Purification and characterization of HIV-1 reverse transcriptase having a 1:1 ratio of p66 and p51 subunits. Protein Expr Purif. 1994 Dec;5(6):614–621. [PubMed]
  • Tantillo C, Ding J, Jacobo-Molina A, Nanni RG, Boyer PL, Hughes SH, Pauwels R, Andries K, Janssen PA, Arnold E. Locations of anti-AIDS drug binding sites and resistance mutations in the three-dimensional structure of HIV-1 reverse transcriptase. Implications for mechanisms of drug inhibition and resistance. J Mol Biol. 1994 Oct 28;243(3):369–387. [PubMed]
  • Tucker TJ, Lyle TA, Wiscount CM, Britcher SF, Young SD, Sanders WM, Lumma WC, Goldman ME, O'Brien JA, Ball RG, et al. Synthesis of a series of 4-(arylethynyl)-6-chloro-4-cyclopropyl-3,4-dihydroquinazolin-2(1H)-ones as novel non-nucleoside HIV-1 reverse transcriptase inhibitors. J Med Chem. 1994 Jul 22;37(15):2437–2444. [PubMed]
  • Wu JC, Warren TC, Adams J, Proudfoot J, Skiles J, Raghavan P, Perry C, Potocki I, Farina PR, Grob PM. A novel dipyridodiazepinone inhibitor of HIV-1 reverse transcriptase acts through a nonsubstrate binding site. Biochemistry. 1991 Feb 26;30(8):2022–2026. [PubMed]
  • YONETANI T, THEORELL H. STUDIES ON LIVER ALCOHOL HYDROGENASE COMPLEXES. 3. MULTIPLE INHIBITION KINETICS IN THE PRESENCE OF TWO COMPETITIVE INHIBITORS. Arch Biochem Biophys. 1964 Jul 20;106:243–251. [PubMed]

Articles from Antimicrobial Agents and Chemotherapy are provided here courtesy of American Society for Microbiology (ASM)

Formats:

Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...

Links

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...