      Document 0014
 DOCN  DRG0014
 UNIQUE IDENTIFIER        DRG-0233
 NAME OF SUBSTANCE        Indinavir sulfate [AIDS Therapies 1995 Sep]
 STANDARD CHEMICAL NAME   [1S-(1alpha(alphaS*,gammaR*,delta(R*)),2alpha-
                          ))-N- (2,3-dihydro-2-hydroxy-1H-inden-1-yl)-
                          thyl)-4-(3-pyridinylmethyl)-1-piperazinepenta-
                          namide monohydrate [FDA 246A]
 SYNONYMS                 Crixivan [Merck & Co brochure 1995]
 SYNONYMS                 MK-639 [MeSH]
 SYNONYMS                 L-735,524 [MeSH]
 PROTOCOL ID NUMBERS      FDA 246D
 PROTOCOL ID NUMBERS      FDA 246A
 PROTOCOL ID NUMBERS      FDA 246E
 PROTOCOL ID NUMBERS      NIAID ACTG 320
 PROTOCOL ID NUMBERS      NCI 95 C-163
 SECONDARY SOURCE ID      MK-639 [AIDS Therapies 1995 Sep]
 SECONDARY SOURCE ID      L-735,524 [AIDS Therapies 1995 Sep]
 PHARMACOLOGICAL ACTION   MODE OF ACTION: Inhibits the HIV
                          protease-mediated cleavage of the viral
                          precursor polyproteins that results in
                          production of noninfectious progeny viral
                          particles. Specifically, the hydroxy group of
                          the hydroxyaminopentane amide moiety of
                          indiavir sulfate ligates to the carboxy
                          groups of the essential aspartyl 25 and 25'
                          enzymic residues. Also, the amide oxygens of
                          indinavir undergo hydrogen bonding to the
                          backbone amide nitrogen of Ile-50 and Ile-50'
                          via an intervening water molecule. In a
                          previous study, urinary excretion of
                          indinavir sulfate and its metabolites
                          represented a minor pathway of elimination.
                          Indinavir sulfate is effective against
                          viruses resistant to reverse transcriptase
                          inhibitors and is synergistically active when
                          used in combination with reverse
                          transcriptase inhibitors. [Proc Natl Acad Sci
                          USA 1994 Apr 26;91(9)] [J Biol Chem 1994 Oct
                          21;269(42)] [Drug Metab Dispos 1995
                          Feb;23(2)]
 DISEASES STUDIED/TREATED Primary HIV infection [Prog Abst Intersci
                          Conf Antimicrob Agents Chemother 1994 Oct]
 DISEASES STUDIED/TREATED FDA approved 3/14/96 for use alone or in
                          combination with nucleoside analogues for
                          treatment of HIV infection in adults [Merck &
                          Co Package Insert 3/96]
 CLASSIFICATION CODE      Protease inhibitor [AIDS Therapies 1995 Sep]
 CLASSIFICATION CODE      Antiretroviral [AIDS Therapies 1995 Sep]
 ADVERSE EFFECTS          Adverse effects include reversible changes in
                          liver function tests, primarily bilirubin.
                          [Natl Conf Hum Retroviruses Relat Infect
                          (2nd) 1995]
 CHEMICAL/PHYSICAL DATA   DRUG DESCRIPTION: Hydroxyaminopentane amide
                          class of peptidomimetics [J Biol Chem 1995
                          Sep 15;270(37)]
 CHEMICAL/PHYSICAL DATA   MOLECULAR FORMULA: C36H47N5O4.H2O [FDA 246A]
 CHEMICAL/PHYSICAL DATA   MOLECULAR WEIGHT: 631.81 [FDA 246A]
 SUBSTANCE DELIVERY DATA  DOSAGE FORM: 100 mg capsules. [FDA 246A]
 SUBSTANCE DELIVERY DATA  MODE OF DELIVERY: Oral. [Prog Abst Intersci
                          Conf Antimicrob Agents Chemother 1994 Oct]
 MANUFACTURERS            Merck Research Laboratories
 REFERENCES               Gulnik SV, Suvorov LI, Liu B, Yu B, Anderson
                          B, Mitsuya H, Erickson JW. Kinetic
                          characterization and cross-resistance
                          patterns of HIV-1 protease mutants selected
                          under drug pressure. Biochemistry. 1995 Jul
                          25;34(29):9282-7.
 REFERENCES               Condra JH, Schleif WA, Blahy OM, Gabryelski
                          LJ, Graham DJ, Quintero JC, Rhodes A, Robbins
                          HL, Roth E, Shivaprakash M, et al. In vivo
                          emergence of HIV-1 variants resistant to
                          multiple protease inhibitors [see comments].
                          Nature. 1995 Apr 6;374(6522):569-71.
 REFERENCES               Woolf E, Au T, Haddix H, Matuszewski B.
                          Determination of L-735,524, an human
                          immunodeficiency virus protease inhibitor, in
                          human plasma and urine via high-performance
                          liquid chromatography with column switching.
                          J Chromatogr A. 1995 Feb 10;692:(1-2):45-52.
 REFERENCES               Condra JH, Schleif WA, Blahy OM, Gabryelski
                          LJ, Graham DJ, Quintero JC, Rhodes A, Tobbins
                          HL, Roth E, Shivaprakash M, et al. Mutations
                          in HIV protease conferring resistance to
                          inhibitor L-735,524. Natl Conf Hum
                          Retroviruses Relat Infect (2nd). 1995 Jan 29-
                          Feb 2;:88.
 REFERENCES               Balani SK, Arison BH, Mathai L, Kauffman LR,
                          Miller RR, Stearns RA, Chen IW, Lin JH.
                          Metabolites of L-735,524, a potent HIV-1
                          protease inhibitor, in human urine. Drug
                          Metab Dispos. 1995 Feb;23(2):266-70.
 REFERENCES               St.Clair MH, Pennington KN, Rooney J, Barry
                          DW. In vitro comparison of selected
                          triple-drug combinations for suppression of
                          HIV-1 replication: the Inter-Company
                          Collaboration Protocol. J Acquir Immune Defic
                          Syndr Hum Retrovirol. 1995;10 Suppl 2:S83-91.
 REFERENCES               Mellors J, Steighbigel R, Gulick R, Frank I,
                          Berry P, McMahon D, Fuhrer J, Farthing C,
                          Hildebrand C, Schleif W, et al. A randomized
                          double blind study of the oral 4 HIV protease
                          inhibitor, L-735,524 vs. zidovudine (ZDV) in
                          p24 antigenemic, HIV-1 infected patients with
                          less than 500 CD4 cells/mm3. Natl Conf Hum
                          Retroviruses Relat Infect (2nd). 1995 Jan
                          29-Feb 2;88.
 REFERENCES               Stein DS, Fish DG, Chodakewitz J, Emini E,
                          Hildebrand C, Preston SL, Martineau GL,
                          Drusango GL. A 24 week open label phase 1
                          evaluation of the HIV protease inhibitor
                          L735524. Natl Conf Hum Retroviruses Relat
                          Infect (2nd). 1995 Jan 29-Feb 2;167.
 REFERENCES               Dorsey BD, Levin RB, McDaniel SL, Vacca JP,
                          Guare JP, Darke PL, Zugay JA, Emini EA,
                          Schleif WA, Quintero JC, et al. L-735,524:
                          the design of a potent and orally
                          bioavailable HIV protease inhibitor. J Med
                          Chem. 1994 Oct 14;37(21):3443-51.
 REFERENCES               Vasavanonda S, Bilello JA, Drusano GL,
                          Denissen J, Johnson M, Clement J, Robins T.
                          Serum binding effects on HIV protease
                          inhibitors. Natl Conf Hum Retroviruses Relat
                          Infect (1st). 1993 Dec 12-16;:129.
 ENTRY MONTH              9510
 LAST REVISION DATE       960514
 

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