      Document 0146
 DOCN  DRG0146
 UNIQUE IDENTIFIER        DRG-0101
 NAME OF SUBSTANCE        L-697,639 [J Med Chem 1992 Oct 16;35(21)]
 REGISTRY NUMBER          135525-77-8
 STANDARD CHEMICAL NAME   3-(((4,7-dimethylbenzoxazol-2-yl)methyl)amino-
                          ) -5-ethyl-6-methylpyridin-2(1H)-one [J Med
                          Chem 1992 Oct 16;35(21)]
 SYNONYMS                 2(1H)-Pyridinone,
                          3-(((4,7-dimethyl-2-benzoxazolyl)methyl)amino-
                          )-5-ethyl-6-methyl [MeSH]
 PROTOCOL ID NUMBERS      NIAID 91 I-41
 SECONDARY SOURCE ID      DRG
 PHARMACOLOGICAL ACTION   MODE OF ACTION: L-697,639 and its congeners
                          are specifically active against the reverse
                          transcriptase of HIV-1, but not against the
                          reverse transcriptases of HIV-2 or any other
                          retroviruses. Nor are they active against any
                          of the cellular DNA polymerases. These
                          HIV-1-specific RT inhibitors seem to interact
                          with a specific target site (YQYMDDLY) at
                          positions 181-188, which is distinct from,
                          but functionally and spatially related to,
                          the substrate (dNTP) binding site. The
                          tyrosine residues Y181 and Y188 play a
                          crucial role in the interaction of L-697,639
                          and its cogeners with their target
                          interaction of L-697,639 and its cogeners
                          with their target site. The HIV-1-specific RT
                          inhibitors have proven to inhibit the
                          replication of various HIV-1 strains,
                          including AZT-resistant HIV-1 strains in
                          different cell culture systems, including
                          peripheral blood lymphocytes and
                          monocyte/macrophages. In vitro they exhibit
                          selectivity indexes of up to 5 orders of
                          magnitude, which means that they are
                          inhibitory to virus replication in cell
                          culture at concentrations that are up to
                          100,000 times lower than the concentrations
                          at which they are toxic to the host cells. As
                          a rule, the HIV-1-specific RT inhibitors are
                          orally bioavailable, as has been demonstrated
                          in rats, dogs, monkeys, and humans. They
                          sustain plasma drug levels that are well
                          above the concentration required to inhibit
                          virus replication in cell culture. L-697,639
                          inhibited HIV-1 RT activity in a
                          concentration-dependent manner with IC50
                          values in the 20-600nm range, depending upon
                          the template-primer substrate. At 300 muM,
                          however, these compounds did not inhibit ten
                          other enzyme activities. These molecules were
                          reversible dead-end inhibitors which gave
                          mixed-type inhibition patterns with respect
                          to dGTP and TTP as well as to rC.dG and
                          rA.dT. L-697,639 inhibited by at least 95%
                          the spread of HIV-1 infection at
                          concentrations of 25-200 nM. The potential
                          clinical usefulness of this compound as a
                          monotherapeutic agent may be limited by the
                          selection of inhibitor-resistant viral
                          variants. [Med Res Rev 1993 May;13(3)]
                          [Antimicrob Agents Chemother 1993 May;37(5)]
                          [J Med Chem 1992 Oct 16;35(21)]
 DISEASES STUDIED/TREATED Primary HIV infection [Med Res Rev 1993
                          May;13(3)]
 CLASSIFICATION CODE      Antiretroviral [J Med Chem 1992 Oct
                          16;35(21)]
 SUBSTANCE INTERACTIONS   Interacts with other experimental drugs and
                          antiretroviral drugs. [NIAID 91 I-41]
 ADVERSE EFFECTS          Some patients have complained of headaches.
                          Possible toxic effects following 8 weeks of
                          oral 25 mg twice daily therapy were reported
                          in a patient. These effects included
                          tinnitus, retinal cotton wool spots,
                          testicular and tonsillar ulcerative lesions.
                          [AmFAR Tx Dir April, 1991] [AIDS 1992
                          June;6(6)]
 CONTRAINDICATIONS        Contraindicated in the presence of a recent
                          history of fever. [AmFAR Tx Dir April, 1991]
 CHEMICAL/PHYSICAL DATA   DRUG DESCRIPTION: Pyridinone derivatives
                          [Antimicrob Agents Chemother 1993 May;37(5)]
                          [Int Conf AIDS 1991 Jun 16-21;7(2): abstract
                          no. W.A.1061]
 CHEMICAL/PHYSICAL DATA   DRUG DESCRIPTION: Part of a novel series of
                          non-nucleoside, potent and selective HIV-1 RT
                          inhibitors [Int Conf AIDS 1991 Jun
                          16-21;7(2): abstract no. W.A. 1061]
                          [Antimicrob Agents Chemother 1993 May;37(5)]
 CHEMICAL/PHYSICAL DATA   DRUG DESCRIPTION: Developed from a screening
                          lead through a synthetic program and
                          judicious SAR analysis [Int Conf AIDS 1991
                          June 16-21;7(2)] [Antimicrob Agents Chemother
                          1993 May;37(5)]
 CHEMICAL/PHYSICAL DATA   MOLECULAR FORMULA: C18H21N3O2 [CHEMLINE]
 SUBSTANCE DELIVERY DATA  MODE OF DELIVERY: Oral. [AmFAR Tx Dir April,
                          1991]
 MANUFACTURERS            Merck, Sharpe & Dohme
 REFERENCES               Van Hecken A, Depre M, De Lepeleire I, Laskin
                          O, Au T, Woolf E, Yeh KC, De Schepper PJ.
                          Human pharmacokinetics and tolerability of
                          L-697,639, a non-nucleoside HIV-1 reverse
                          transcriptase inhibitor. Int J Clin Pharmacol
                          Res. 1994;14(2):45-50.
 REFERENCES               De Clerg E. HIV-1-specific RT inhibitors:
                          highly selective inhibitors of human
                          immunodeficiency virus type 1 that are
                          specifically targeted at the viral reverse
                          transcriptase. Med Res Rev. 1993
                          May;13(3):229-58.
 REFERENCES               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):3792-802.
 REFERENCES               Nunberg JH, Quintero JC, Schleif WA, Emini
                          EA, Friedman PA, Raison JM. HIV-1 specific
                          pyridinone reverse transcriptase inhibitors:
                          III. Synergism in the combined in vitro use
                          with nucleoside analogs. Int Conf AIDS. 1991
                          Jun 16-21;7(2):95 (abstract no. W.A.1012).
 REFERENCES               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
                          USA. 1991 Aug 1;88(15):6863-7.
 REFERENCES               Goldman ME, O'Brien JA, Ruffing TL, Stern AM,
                          Gaul SL, Saari WS, Wai JS, Hoffman J, Rooney
                          CS, Quintero JC, et al. HIV-1 specific
                          pyridinone RT inhibitors: I. Preclinical
                          biological characterization of two
                          investigational new drugs. Int Conf AIDS.
                          1991 Jun 16-21;7(1):74 (abstract no.
                          TU.A.67).
 ENTRY MONTH              9102
 LAST REVISION DATE       951213
 

SOURCE: National Library of Medicine, Bethesda, MD.  Distributed by AEGIS.
