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Chemical Compound Review

DISOXARIL     5-[7-[4-(4,5-dihydro-1,3- oxazol-2...

Synonyms: Disoxarilo, Disoxarilum, Compound IV, CHEMBL283639, SureCN147146, ...
 
 
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Disease relevance of C06496

  • WIN 51711 and WIN 52084 are structurally related, antiviral compounds that inhibit the replication of rhino (common cold) viruses and related picornaviruses [1].
  • We have previously described the use of an uncoating inhibitor, WIN 51711, to select drug-resistant mutants of the Sabin strain of poliovirus type 3 [2].
  • WIN 51711-dependent mutants of poliovirus type 3: evidence that virions decay after release from cells unless drug is present [3].
  • In plaque reduction assays, WIN 51711 reduced plaque formation by 9 enteroviruses and 33 rhinoviruses, with MICs of 0.004 to 0.17 and 0.004 to 6.2 micrograms/ml, respectively [4].
  • Use of WIN 51711 to prevent echovirus type 9-induced paralysis in suckling mice [5].
 

Psychiatry related information on C06496

  • Compound IV demonstrated activity in the maximal electroshock (MES) and subcutaneous pentylenetetrazol (scPTZ) tests in mice, with low neurotoxicity [6].
 

High impact information on C06496

  • (15R)-10,10-Difluoro-TXA2 (compound II), (5E)-10,10-difluoro-TXA2 (compound III), and (5E,15R)-10,10-difluoro-TXA2 (compound IV) were antagonists of platelet aggregation stimulated by compound I (Kd = 98 +/- 46 nM, 140 +/- 42 nM, and 1450 +/- 350 nM, respectively) [7].
  • Twenty-two spontaneous mutants of the Sabin strain of poliovirus type 3 were selected for drug resistance by plating on HeLa cell monolayers in the presence of WIN 51711, an uncoating inhibitor [3].
  • The structures of complexes of HRV14 with SCH 38057 and WIN 51711 are compared [8].
  • The increased entry of labeled heparin promoted by virus entry is not blocked by these agents, indicating that poliovirus binds to its receptor and is internalized along with heparin in endosomes in the presence of WIN 51711, DEPC, or Ro 09-0410 [9].
  • We noticed that one of these antiviral compounds, WIN 51711, had an antiviral spectrum clearly distinctive from a consensus spectrum or other capsid-binding compounds, although all of them were shown to share the same binding site [10].
 

Chemical compound and disease context of C06496

  • Sucrose gradient sedimentation of lysates from whole cells infected with [3H]uridine-labeled poliovirus showed that poliovirions remained intact in the presence of WIN 51711, but were uncoated in the absence of drug [11].
  • The half-life of the N antigen of Mahoney and Sabin 1 virions was extended 50- to 250-fold by either 10 microM WIN 51711 or R 78206 [12].
 

Biological context of C06496

  • The two most effective inhibitors, an alpha-keto-beta-amino ester (compound IV) and a thioamine (compound VIII), exhibited IC50 values of 1.9 +/- 0.9 and 0.19 +/- 0.12 microM (mean +/- SD, n = 4), respectively [13].
  • The ethanol extract of E. rutaecarpa also inhibited LPS-induced NO production (with an IC(50) of around 0.8 mug/ml) and iNOS upregulation in microglial cells that was partially mimicked by compounds I, II, and III, but not compound IV [14].
  • Three skin tumours and 2 preneoplastic lesions were found among 9 mice receiving the compound IV, the agent giving the slowest chemical alkylation reactions [15].
 

Anatomical context of C06496

  • In the presence of WIN 51711, exposure of neutral red-encapsidated virus-infected cells to light at 3 h postinfection resulted in a 3-log reduction in the number of infectious centers, indicating that WIN 51711 maintained the viral RNA in the encapsidated state after penetrating the cell membrane [11].
  • Compound IV displayed the highest quantum yield (0.28) and most rapid photolysis rate (1980 s-1) measured under near physiological conditions, pH 7.0, 22 degrees C. Biological properties of the compounds were examined in smooth muscle from rat caudal artery [16].
  • The effect against trypanosomatids, which suggests high activity of compound IV against promastigotes of L. amazonensis and amastigotes of T. cruzi, stimulated further studies in vitro with amastigotes interiorized in macrophages and with in vivo models [17].
  • Disoxaril [WIN 51711, 5-[7-[4(4,5-dihydro-2-oxazolyl)phenoxy]heptyl]-3- methylisoxazole] inhibits the replication of polioviruses types 1 and 2 in HeLa cells by stabilizing the virus capsid, which results in the inhibition of the pH-dependent viral uncoating in endosomes and/or lysosomes [18].
  • 5. In mouse pancreatic beta-cells, measurement of KATP-channel activity in cell-attached patches and recording of insulin release displayed much higher EC50 values for compound IV than inside-out patch experiments [19].
 

Associations of C06496 with other chemical compounds

  • This alternative assignment is shown to require compensating effects in the pH region around 8 such that the formation of (Cys-25)-S-/(His-159)-Im across pKa 8.0-8.5 is without net kinetic effect in the reactions of simple 2-pyridyl disulphides such as compound (IV) and 2,2'-dipyridyl disulphide (II) [20].
  • Although the activities of certain drug-metabolizing enzymes were increased after oral administration of compound IV to rats, these effects were less prominent than those of phenytoin (PHT) and carbamazepine (CBZ) [6].
  • When administered intraperitoneally (i.p.) at doses of 100, 300, or 600 mg/kg to peritoneally (i.p.) at doses of 100, 300, or 600 mg/kg to rats, compound IV had no effect on levels of gamma-aminobutyric acid (GABA) or on GABA-T activity in whole brain [6].
  • The type of antagonism exhibited by three novel bradykinin (BK) antagonists, D-Arg-[Hyp3,Thi5,D-Tic7,Oic8]BK (HOE 140, compound I), D-Arg-[Hyp3,D-Tic7,Oic8]BK (compound II) and [Arg(Tos)1,Hyp3,Thi5,D-Tic7,Oic8]BK (compound III), was compared with that of a conventional antagonist, D-Arg-[Hyp2,Thi5,8,D-Phe7]BK (compound IV), on the guinea-pig ileum [21].
  • Incubation of compound (III) with rat kidney homogenate in a Tris buffer (pH 8), formed compound (II) in 80% yield possibly via compound (IV) [22].
 

Gene context of C06496

  • When tested in vitro, compound IV had no effect on rat brain GABA-T at a drug concentration of 100 microM [6].
  • The principal mode of action of compound IV does not appear to be an interaction with the GABAA receptor complex, and other mechanisms, involving excitatory amino acid neurotransmission, will have to be considered in future investigations of the anticonvulsant activity of this compound [6].
  • Compound IV was nearly as cytotoxic as DDP [23].
  • Finally, the derivative with a reversed configuration of the 17-spirolactone ring (compound IV) had no biological activity in vivo and no affinity for the MCR [24].
 

Analytical, diagnostic and therapeutic context of C06496

  • Oral administration of WIN 51711 twice daily beginning 72 hr after infection was the most-effective dosage regimen, with doses as low as 3 mg/kg preventing paralysis in 75% of the animals [5].
  • Injection of 17-35 MBq (5-28 mg) of the labelled compound IV was followed by imaging, using a gamma camera, with particular reference to the kidneys, liver, and tumour site [25].
  • Two compounds of the first set were tentatively identified as 9,10,11,12,13,14,19,20-octanor-capsorubin (compound II) and 9,10,11,12,13,14,19,20-octanor-5,6-epoxide-capsanthin (compound IV), after isolation by semipreparative HPLC and analysis by EI-MS [26].
  • Confirmation of the anxiolytic activity of compound IV in animal models was obtained in 3 separate clinical trials in anxious patients [27].

References

  1. The site of attachment in human rhinovirus 14 for antiviral agents that inhibit uncoating. Smith, T.J., Kremer, M.J., Luo, M., Vriend, G., Arnold, E., Kamer, G., Rossmann, M.G., McKinlay, M.A., Diana, G.D., Otto, M.J. Science (1986) [Pubmed]
  2. Distribution of drug resistance mutations in type 3 poliovirus identifies three regions involved in uncoating functions. Mosser, A.G., Sgro, J.Y., Rueckert, R.R. J. Virol. (1994) [Pubmed]
  3. WIN 51711-dependent mutants of poliovirus type 3: evidence that virions decay after release from cells unless drug is present. Mosser, A.G., Rueckert, R.R. J. Virol. (1993) [Pubmed]
  4. In vitro activity of WIN 51711, a new broad-spectrum antipicornavirus drug. Otto, M.J., Fox, M.P., Fancher, M.J., Kuhrt, M.F., Diana, G.D., McKinlay, M.A. Antimicrob. Agents Chemother. (1985) [Pubmed]
  5. Use of WIN 51711 to prevent echovirus type 9-induced paralysis in suckling mice. McKinlay, M.A., Frank, J.A., Benziger, D.P., Steinberg, B.A. J. Infect. Dis. (1986) [Pubmed]
  6. Anticonvulsant activities of 4-bromobenzaldehyde semicarbazone. Dimmock, J.R., Baker, G.B. Epilepsia (1994) [Pubmed]
  7. Difluorothromboxane A2 and stereoisomers: stable derivatives of thromboxane A2 with differential effects on platelets and blood vessels. Morinelli, T.A., Okwu, A.K., Mais, D.E., Halushka, P.V., John, V., Chen, C.K., Fried, J. Proc. Natl. Acad. Sci. U.S.A. (1989) [Pubmed]
  8. Structure determination of antiviral compound SCH 38057 complexed with human rhinovirus 14. Zhang, A., Nanni, R.G., Li, T., Arnold, G.F., Oren, D.A., Jacobo-Molina, A., Williams, R.L., Kamer, G., Rubenstein, D.A., Li, Y. J. Mol. Biol. (1993) [Pubmed]
  9. Inhibitors of poliovirus uncoating efficiently block the early membrane permeabilization induced by virus particles. Almela, M.J., González, M.E., Carrasco, L. J. Virol. (1991) [Pubmed]
  10. Two groups of rhinoviruses revealed by a panel of antiviral compounds present sequence divergence and differential pathogenicity. Andries, K., Dewindt, B., Snoeks, J., Wouters, L., Moereels, H., Lewi, P.J., Janssen, P.A. J. Virol. (1990) [Pubmed]
  11. Prevention of rhinovirus and poliovirus uncoating by WIN 51711, a new antiviral drug. Fox, M.P., Otto, M.J., McKinlay, M.A. Antimicrob. Agents Chemother. (1986) [Pubmed]
  12. A comparison of WIN 51711 and R 78206 as stabilizers of poliovirus virions and procapsids. Rombaut, B., Andries, K., Boeyé, A. J. Gen. Virol. (1991) [Pubmed]
  13. Potent and selective inhibitors of leukotriene A4 hydrolase: effects on purified enzyme and human polymorphonuclear leukocytes. Wetterholm, A., Haeggström, J.Z., Samuelsson, B., Yuan, W., Munoz, B., Wong, C.H. J. Pharmacol. Exp. Ther. (1995) [Pubmed]
  14. Anti-inflammatory effects and mechanisms of the ethanol extract of Evodia rutaecarpa and its bioactive components on neutrophils and microglial cells. Ko, H.C., Wang, Y.H., Liou, K.T., Chen, C.M., Chen, C.H., Wang, W.Y., Chang, S., Hou, Y.C., Chen, K.T., Chen, C.F., Shen, Y.C. Eur. J. Pharmacol. (2007) [Pubmed]
  15. Effects of some pyrrolic and dihydropyrrolizine esters on mouse skin: a preliminary study. Mattocks, A.R., Cabral, J.R. Tumori. (1979) [Pubmed]
  16. Rapid release of an alpha-adrenergic receptor ligand from photolabile analogues. Walker, J.W., Martin, H., Schmitt, F.R., Barsotti, R.J. Biochemistry (1993) [Pubmed]
  17. 3-[4'-bromo-(1,1'-biphenyl)-4-yl]-N, N-dimethyl-3-(2-thienyl)-2-propen-1-amine: synthesis, cytotoxicity, and leishmanicidal, trypanocidal and antimycobacterial activities. de Souza, A.O., Hemerly, F.P., Busollo, A.C., Melo, P.S., Machado, G.M., Miranda, C.C., Santa-Rita, R.M., Haun, M., Leon, L.L., Sato, D.N., de Castro, S.L., Durán, N. J. Antimicrob. Chemother. (2002) [Pubmed]
  18. Inhibition of poliovirus uncoating by disoxaril (WIN 51711). Zeichhardt, H., Otto, M.J., McKinlay, M.A., Willingmann, P., Habermehl, K.O. Virology (1987) [Pubmed]
  19. Location of the sulphonylurea receptor at the cytoplasmic face of the beta-cell membrane. Schwanstecher, M., Schwanstecher, C., Dickel, C., Chudziak, F., Moshiri, A., Panten, U. Br. J. Pharmacol. (1994) [Pubmed]
  20. Ionization characteristics of the Cys-25/His-159 interactive system and of the modulatory group of papain: resolution of ambiguity by electronic perturbation of the quasi-2-mercaptopyridine leaving group in a new pyrimidyl disulphide reactivity probe. Mellor, G.W., Thomas, E.W., Topham, C.M., Brocklehurst, K. Biochem. J. (1993) [Pubmed]
  21. Analysis of the antagonistic actions of HOE 140 and other novel bradykinin analogues on the guinea-pig ileum. Griesbacher, T., Lembeck, F. Eur. J. Pharmacol. (1992) [Pubmed]
  22. Preparation and characterization of S-[2-carboxy-1-(1H-imidazol-4-yl)ethyl]glutathione and its derivatives as proposed precursors of S-[2-carboxy-1-(1H-imidazol-4-yl)ethyl]cysteine, a compound found in human urine. Kinuta, M., Ubuka, T., Yao, K., Yamada, S., Yukihiro, K., Tomozawa, M. Biochim. Biophys. Acta (1993) [Pubmed]
  23. Synthesis and cytotoxicity of platinum(II) complexes of 3-aminocyclopentanespiro-5-hydantoin and 3-aminocycloheptanespiro-5-hydantoin. Kushev, D., Naydenova, E., Popova, J., Maneva, L., Grancharov, K., Spassovska, N. Z. Naturforsch., C, J. Biosci. (2003) [Pubmed]
  24. The renal action of spirorenone and other 6 beta,7 beta; 15 beta,16 beta-dimethylene-17-spirolactones, a new type of steroidal aldosterone antagonists. Casals-Stenzel, J., Buse, M., Wambach, G., Losert, W. Arzneimittel-Forschung. (1984) [Pubmed]
  25. In vivo distribution studies of radioactively labelled platinum complexes; cis-dichlorodiammine platinum(II), cis-trans-dichlorodihydroxy-bis-(isopropylamine) platinum(IV), cis-dichloro-bis-cyclopropylamine platinum(II), and cis-diammine 1,1-cyclobutanedicarboxylate platinum(II) in patients with malignant disease, using a gamma camera. Owens, S.E., Thatcher, N., Sharma, H., Adam, N., Harrison, R., Smith, A., Zaki, A., Baer, J.C., McAuliffe, C.A., Crowther, D. Cancer Chemother. Pharmacol. (1985) [Pubmed]
  26. Thermal degradation products formed from carotenoids during a heat-induced degradation process of paprika oleoresins (Capsicum annuum L.). Pérez-Gálvez, A., Rios, J.J., Mínguez-Mosquera, M.I. J. Agric. Food Chem. (2005) [Pubmed]
  27. Non-benzodiazepine anxiolytics: potential activity of phenylpiperazines without 3H-diazepam displacing action. Lloyd, K.G., Depoortere, H., Scatton, B., Schoemaker, H., Zivkovic, B., Manoury, P., Langer, S.Z., Morselli, P.L., Bartholini, G. Pharmacol. Biochem. Behav. (1985) [Pubmed]
 
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