Oximes: A new class of methoxytetrahydropyranyl inhibitors of leukotriene biosynthesis with high in vitro and in vivo potency

Bioorganic and Medicinal Chemistry Letters

Volumn 6, Issue 2, 1996, Pages 127-132

  Plé, Patrick A ^a   Geoffrey, T ^a   Bird, C ^a  

^a Centre de Recherches   (France)

Author keywords

[No Author keywords available]

Indexed keywords

6 [5 FLUORO 3 (4 METHOXYTETRAHYDROPYRAN 4 YL) PHENOXYMETHYL] 1 METHYL 2 QUINOLINONE; 6 [[3 FLUORO 5 (3,4,5,6 TETRAHYDRO 4 METHOXY 2H PYRAN 4 YL)]PHENOXYMETHYL] 1 METHYL 2 QUINOLONE; ARACHIDONATE 5 LIPOXYGENASE; LEUKOTRIENE B4; OXIME DERIVATIVE; UNCLASSIFIED DRUG;

ANIMAL MODEL; ARTICLE; CONTROLLED STUDY; DRUG SOLUBILITY; DRUG SYNTHESIS; ENZYME INHIBITION; ERYTHROCYTE; HUMAN; HUMAN CELL; INFLAMMATION; NONHUMAN; ORAL DRUG ADMINISTRATION; PKA; QUANTITATIVE STRUCTURE ACTIVITY RELATION; RAT;

EID: 0342592259     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/0960-894X(95)00578-H     Document Type: Article

References (14)

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3. a) Initial clinical data on 5-LO inhibitor Zileuton (Abbott) have shown efficacy on mild-to-moderate asthma. Isreal, E.; Rubin, P.; Kemo, J.P.; Grossman, J.; Pierson, W.; Siegel, S.C.; Tinkelman, D.; Murray, J.J.; Busse, W.; Segal, A.T.; Fish, J.; Kaiser, H.B.; Ledford, D.; Wenzel, S.; Rosenthal, R.; Cohn, J.; Lanni, C.; Pearlman, H.; Karahalios, P.; Drazen, J.M. Ann. Intern. Med. 1993, 119, 1059-1066.
4. b) Chung, K. F. Eur. Respir. J., 1995, 8, 1203-13
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6. Crawley, G. C.; Dowell, R. I.; Edwards, P. N.; Foster, S. J.; McMillan, R. M.; Walker, E. R. H.; Waterson, D.; Bird, T. G. C.; Bruneau, P.; Girodeau, J-M. J. Med. Chem. 1992, 35, 2600-2609.
7. Crawley, G. C.; Bird, T. G. C.; Bruneau, P.; Dowell, R. I.; Edwards, P. N.; Foster, S. J.; Girodeau, J. M.; McMillan, R. M.; Walker, E. R. H.; Waterson, D. J. Lipid Mediators 1993, 6, 249-57.
8. Foster, S. J.; Bruneau, P.; Walker, E. R. H.; McMillan, R. M. Br. J. Pharmacol. 1990, 99, 113-118.
9. For the syntheses of the molecules presented here see the european patent EP 0555068 (11AUG93).
10. E/Z refers to a roughly equimolar mixture of E and Z oximes. E or Z refers to one single isomer of unknown configuration. Unless otherwise specified, the oximes presented in this paper have the E configuration. Z isomers of unsubstituted oximes equilibrate very quickly in solution in the presence of light or mild acid to give the E oxime. Alkylation of the Z isomer with bromoacetonitrile give stable compound whose biological results are very similar to the E isomers. Hence, the relative stereochemistry of the oximes does not seem to be of importance for 5-LO inhibition.
11. The pKas were measured according to: Kurtz, P. A.; D'Silva, T. D. J. J. Pharm. Sci. 1987, 76, 599-610.
12. Replacement of the fluorophenyl central ring by a thiophenyl had been shown to be sometimes beneficial for in vivo activity in the oxime series (unpublished results).
13. Crawley, G. C.; Briggs, M. T.; Dowell, R. I.; Edwards, P. N.; Hamilton, P. M.; Kingston, J. F.; Oldham, K.; Waterson, D.; Whalley, D. P. J. Med. Chem. 1993, 36, 295-6.
14. -2 M phosphate buffer, pH 7.4, containing 0.15 M NaCl).