      Document 0028
 DOCN  DRG0028
 UNIQUE IDENTIFIER        DRG-0219
 NAME OF SUBSTANCE        Kynostatin 272 [MeSH]
 REGISTRY NUMBER          147318-81-8
 STANDARD CHEMICAL NAME   4-Thiazolidinecarboxamide,
                          N-(1,1-dimethylethyl)-3-(2-hydroxy-3-
                          ((2-(((5-isoquinolinyloxy)acetyl)amino)-3-
                          (methylthio)-1-ox
                          opropyl)amino)-1-oxo-4-phenylbutyl)-,
                          (4R-(3(2S*,3S*(R*)),4R*)) [CEMLINE]
 SYNONYMS                 KNI-272 [MeSH]
 SYNONYMS                 Kynostatin 272 [MeSH]
 PROTOCOL ID NUMBERS      NCI 94 C-40
 PROTOCOL ID NUMBERS      NCI 94 C-147
 SECONDARY SOURCE ID      DRG
 PHARMACOLOGICAL ACTION   MODE OF ACTION: Highly potent against HIV
                          protease with little inhibition of other
                          aspartic proteases in a wide spectrum of HIV
                          strains in vitro. In one study, IC50s of
                          KNI-272 against HIV type 1 LAI, RF, and MN,
                          and HIV type 2 ROD were 0.1, 0.02, 0.04 and
                          0.1 microM, respectively, when tested in
                          target CD4+ ATH8 cells. Ratio of 50 percent
                          cytotoxic concentration to IC50 was > 4000,
                          as assessed in peripheral blood mononuclear
                          cells. KNI-272 blocked the posttranslational
                          cleavage of the p55 precursor protein to
                          generate the mature p24 Gag protein in HIV-1
                          infected cells. Data from a later study
                          suggest that decreased virus sensitivity to
                          KNI-272 may develop. Detailed studies of
                          protein binding suggest that in human plasma
                          binding of KNI-272 occurs predominantly to
                          alpha 1-acid glycoprotein.  These studies
                          further suggest that KNI-272 is extensively
                          (98-99 percent) protein bound at
                          concentrations likely to be achieved in the
                          circulation. [Antimicrob Agents Chemother
                          1993 Apr 37(4); Int Conf AIDS 1994 Aug
                          7-12;10(2): (abstract no. 516B); Antimicrob
                          Agents Chemother 1994 May 38(5)]
 DISEASES STUDIED/TREATED Primary HIV infection [Int Conf AIDS 1994 Aug
                          7-12;10(2): (abstract no. 516B)]
 CLASSIFICATION CODE      Protease inhibitor [MeSH]
 CLASSIFICATION CODE      Antiretroviral [NCI 94 C-40]
 ADVERSE EFFECTS          Adverse effects experienced by patients thus
                          far include fatigue, parotitis (inflammation
                          of salivary gland), elevated liver function
                          tests, and elevated amylase without evidence
                          of pancreatitis. [NCI 94 C-40]
 CONTRAINDICATIONS        Contraindicated in pregnant women. [NCI 94
                          C-40]
 CHEMICAL/PHYSICAL DATA   DRUG DESCRIPTION: Transition-state mimetic
                          tripeptide HIV protease inhibitor containing
                          allophenylnorstatine with a
                          hydroxymethylcarbonyl isostere [Int Conf AIDS
                          1994 Aug 7-12;10(2): (abstract no. 516B)]
 CHEMICAL/PHYSICAL DATA   MOLECULAR FORM: C33H41N5O6S2 [CHEMLINE]
 CHEMICAL/PHYSICAL DATA   SOLUBILITY: Extremely low aqueous solubility
                          (4 mcg/ml) [J Pharm Sci 1994 Aug;83(8)]
 SUBSTANCE DELIVERY DATA  DOSAGE FORM: Liquid, capsules, or tablets.
                          [NCI 94 C-40]
 SUBSTANCE DELIVERY DATA  MODE OF DELIVERY: Intravenous; oral. [NCI 94
                          C-40]
 MANUFACTURERS            National Cancer Institute for Japan Energy
                          Corp
 REFERENCES               Chokekijchai S, Shirasaka T, Weinstein JN,
                          Mitsuya H. In vitro anti-HIV-1 activity of
                          HIV protease inhibitor KNI-272 in resting and
                          activated cells: implications for its
                          combined use with AZT or ddI. Antiviral Res.
                          1995 Sep;28(1):25-38.
 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               Sugahara M, Kiriyama A, Hamada Y, Kiso Y,
                          Takada K. Absorption of new HIV-1 protease
                          inhibitor, KNI-272, after intraduodenal and
                          intragastric administrations to rats: effect
                          of solvent. Biopharm Drug Dispos. 1995
                          May;16(4):269-77.
 REFERENCES               Humphrey RW, Mitsuya H, Yarchoan R. HIV
                          protease inhibitors do not prevent cell death
                          during single-cycle HIV infection of CEM-ss
                          cells in vitro. Natl Conf Hum Retroviruses
                          Relat Infect (2nd). 1995 Jan 29-Feb 2;:71.
 REFERENCES               Anderson B, Kageyama S, Ueno T, Shirasaka T,
                          Liu B, Gulnick S, Erickson J, Mitsuya H. In
                          vitro induction HIV-1 with reduced
                          sensitivity to HIV protease inhibitors,
                          KNI-227 and KNI-272. Natl Conf Hum
                          Retroviruses Relat Infect (2nd). 1995 Jan
                          29-Feb 2;:72.
 REFERENCES               Baldwin ET, Bhat TN, Gulnik S, Liu B, Kiso Y,
                          Mitsuya H, Erickson JW. Structure of HIV-1
                          protease with KNI-272: a transition state
                          mimetic inhibitor containing
                          allophenylnorstatine. Adv Exp Med Biol.
                          1995;362:445-9.
 REFERENCES               Kiriyama A, Fujita K, Takemura S, Kuramoto H,
                          Kiso Y, Takada K. Plasma pharmacokinetics and
                          urinary and biliary excretion of a new potent
                          tripeptide HIV-1 protease inhibitor, KNI-272,
                          in rats after intravenous administration.
                          Biopharm Drug Dispos. 1994 Oct;15(7):617-26.
 REFERENCES               Kageyama S, Anderson BD, Hoesterey BL,
                          Hayashi H, Kiso Y, Flora KP, Mitsuya H.
                          Protein binding of human immunodeficiency
                          virus protease inhibitor KNI-272 and
                          alteration of its in vitro antiretroviral
                          activity in the presence of high
                          concentrations of proteins.  Antimicrob
                          Agents Chemother. 1994 May;38(5):1107-11.
 REFERENCES               Kageyama S, Mimoto T, Murakawa Y, Nomizu M,
                          Ford H Jr, Shirasaka T, Gulnik S, Erickson J,
                          Takada K, Hayashi H, et al. In vitro
                          anti-human immunodeficiency virus (HIV)
                          activities of transition state mimetic HIV
                          protease inhibitors containing
                          allophenylnorstatine. Antimicrob Agents
                          Chemother. 1993 Apr;37(4):810-7.
 ENTRY MONTH              9502
 LAST REVISION DATE       960424
 

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