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WO1997008162A1 - Agents anti-tumoraux derives de beta-lapachones - Google Patents

Agents anti-tumoraux derives de beta-lapachones Download PDF

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Publication number
WO1997008162A1
WO1997008162A1 PCT/US1996/013656 US9613656W WO9708162A1 WO 1997008162 A1 WO1997008162 A1 WO 1997008162A1 US 9613656 W US9613656 W US 9613656W WO 9708162 A1 WO9708162 A1 WO 9708162A1
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Prior art keywords
mapachone
cells
substituted
allyl
lapachone
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Ceased
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PCT/US1996/013656
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English (en)
Inventor
Arthur Pardee
Chiang J. Li
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Dana Farber Cancer Institute Inc
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Dana Farber Cancer Institute Inc
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Priority to AU69012/96A priority Critical patent/AU6901296A/en
Publication of WO1997008162A1 publication Critical patent/WO1997008162A1/fr
Priority to US09/028,400 priority patent/US6245807B1/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/78—Ring systems having three or more relevant rings
    • C07D311/92—Naphthopyrans; Hydrogenated naphthopyrans

Definitions

  • the present invention is directed to a method of stimulating the death of prostate tumor cells.
  • the method is used to treat individuals suffering from prostate cancer.
  • Prostate cancer is a serious cause of death worldwide.
  • Androgen independent prostate cancer is presently the most common cancer in men in the United States with 38,000 deaths anticipated for the USA in 1994, and is a significant condition worldwide. Approximately 50% of patients are presented with metastatic disease. However, the only existing treatment for metastatic disease is hormonal therapy, which is not curative. Thus, the metastatic disease is typically fatal.
  • Hormonal therapy consisting of different approaches to blocking the action of androgen on the prostate tumor is effective in controlling only the growth of tumor cells that depend on androgen for growth (hormone-dependent tumor).
  • hormone-dependent tumor inevitably progresses to more advanced hormone-independent tumor, which cannot be controlled by current treatment.
  • Difficulties in treating prostate cancer arise from a variety of reasons. Although such androgen ablation is a standard therapy for metastatic prostate cancer it is rarely entirely successful because in most individuals the cancer is heterogeneous comprising both androgen dependent and androgen independent cancer cells. Thus, the therapy does not eliminate the androgen independent cells.
  • Chemotherapy which has been used to treat a number of other cancers, has not proven successful. This is because the vast majority of these androgen independent cells are not actively proliferating and standard chemotherapeutic agents work by selectively killing actively proliferating cells.
  • Radiotherapy which also is selective for rapidly proliferating cells, has also not proven effective. Surgery has also not proven an effective means for treating advanced disease states. Accordingly, it would be desirable to have new methods for stimulating the death of these slow proliferating cancer cells. It would be particularly desirable to have a new means of treating individuals suffering from prostate cancer, particularly androgen independent cancer.
  • Mapachone (3,4-dihydro-s,3-dimethyl-2H-naphthol[1 ,3-b] pyran- 5,6-clone) is a simple plant product with a chemical structure different from currently used anti-cancer drugs. It is obtained by sulfuric acid treatment of the naturally occurring lapachol, which is readily isolated from Tabebuia avellanedae growing mainly in Brazil, or is easily synthesized from lomatiol, isolated from seeds of lomatia growing in Australia (Hooker, S., et. al., J. Am. Chem. Soc, 58: 1 181 -1 190 (1936); Goncalves de Lima, O., et al., Rev. Inst. Antibiot. Univ. Recife.
  • Mapachone has been shown to have a variety of pharmacological effects. /Mapachone is a topoisomerase I inhibitor but acts by a different mechanism than camptothecin. Numerous ⁇ - lapachone derivatives have been synthesized and tested as anti-viral and anti-parasitic agent (Goncalves, A.M., et al., Mol. Biochem. Parasitology, 1 : 167-176 (1980); Schaffner-Sabba, K., et al., J. Med. Chem., 27:990-994 (1984); Li, C, et al., Proc. Natl. Acad. Sci. USA, 90: 187-1842 (1993)).
  • Mapachone and its derivatives show anti-trypanosomal effects (Goncalves, A.M., et al., supra), the mechanism of which is unclear. It significantly prolongs the survival of mice infected with Rauscher leukemia virus, probably through inhibition of reverse transcriptase (Schaffner-Sabba, K., et al., supra; Schuerch, A.R., et al., J. Biochem., 84: 197-205 (1978)).
  • LTR long terminal repeat
  • Mapachone has also been shown to be a DNA repair inhibitor which sensitizes cells to DNA damaging agents (Boorstein, R.J., et al., Biochem. Biophys. Res.
  • yff-lapachone is well tolerated in dogs, rats, mice, and chickens.
  • the maximum tolerated dose, when given p.o daily for one month, is 200 mg/kg in rats, and 100 mg/kg in dogs. Higher doses cause gastric ulceration and loss of erythrocytes, but not signs of bone marrow suppression (Ciba-Geigy, personal communication). The previous experience with this compound in humans has been limited.
  • R and R are each independently selected from the group consisting of hydrogen, hydroxy, thio (SH), halogen, substituted and unsubstituted alkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted aryl, and substituted and unsubstituted alkoxy, and salts thereof, wherein the dotted double bond between the ring carbons to which R and R, are bonded represent an optional ring double bond.
  • Preferred compounds of formula I include those in which at least one of the substituents R and R, is hydrogen and/or at least one of said substituents is allyl.
  • Specifically preferred compounds include yff-lapachone (i.e., R and R, both being hydrogen), allyl-/?- lapachone, particularly 3-allyl- ⁇ -lapachone (i.e. R being allyl and R, being hydrogen) and 3-bromo-/Mapachone (i.e. R being bromo and R, being hydrogen).
  • the present invention further provides a method for inducing cell apoptosis in vivo which comprises contacting the cell with an effective amount of the compound.
  • the cell is preferably a human prostate cell. More preferably, the cell is a human prostate cancer cell.
  • Figure 1 shows the effect of /Mapachone on survival of human prostate cancer cells O, PC-3 cells; O, DU145 cells. Cell survival was determined by the colony formation assay described below.
  • Figures 2A, 2B, 2C and 2D show induction of apoptosis by ⁇ - lapachone in human prostate cancer cells.
  • DNA laddering typical feature of apoptosis, was induced in PC-3, D 145 (2A) and LNCaP cells (2B).
  • 2A cells were treated with 4 ⁇ W ⁇ /Mapachone for 4 hours, followed by incubation in drug-free medium for 4 hours (lane 2,7), 12 hours (lane 3,8), 20 hours (lane 4,9), 44 hours (lane 5, 10).
  • As controls cells were treated with equal volume of DMSO (lane 1 ,6).
  • LNCaP cells were treated with /Mapachone for 4 hours at concentrations of O ⁇ M (lane 1 ), 0.5 ⁇ M (lane 2), 2 ⁇ M (lane 3), 4 /M (lane 4), followed by drug free incubation for 20 hours.
  • LNCaP cells were treated with or DMSO (2C) or 8 ⁇ M /Mapachone (2D) for 1 hour, followed by incubation in drug-free media for 23 hours before they were subjected to flow cytometric analysis.
  • Figure 3 shows lack of correlation between /Mapachone induced apoptosis and the expression of p53 and bcl-2.
  • Figures 4A, 4B, and 4C shows induction of apoptosis (A) and differentiation in HL-60 cells (B,C) by 0-lapachone.
  • HL-60 cells were treated with 8 ⁇ M Mapachone for 24 hours (lane 1 ). 16 hours (lane 2), 8 hours (lane 3), 4 hours (lane 4), 2 hours (lane 5), 0 hours (lane 6).
  • Cellular DNA was extracted and subjected to gel electrophoresis.
  • HL-60 cells were treated with ethanol (1/1000, v/v) (4B) or
  • Figure 5 shows the effect of /Mapachone on tumor volume.
  • the bar represents episodes of administration of Mapachone.
  • Figure 6 shows the effect in vivo of /Mapachone on prostate tumors AT-3.1.
  • Figure 7 shows the effect in vivo of /Mapachone on prostate tumors AT-3.1.
  • R and R are each independently selected from the group consisting of hydrogen, hydroxy, thio (SH), halogen (e.g. fluoro, chloro and bromo), substituted and unsubstituted aryl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkyl and substituted and unsubstituted alkoxy, and salts thereof, wherein the dotted double bond between the ring carbons to which R and R, are bonded represent an optional ring double bond.
  • the alkyl groups preferably have from 1 to about 15 carbon atoms, more preferably from 1 to about 10 carbon atoms, still more preferably from 1 to about
  • alkyl refers to both cyclic and noncyclic groups, although of course cyclic groups will comprise at least three carbon ring members.
  • Straight or branched chain noncyclic alkyl groups are generally more preferred than cyclic groups.
  • Straight chain alkyl groups are generally more preferred than branched.
  • the alkenyl groups preferably have from 2 to 15 carbon atoms, more preferably from 2 to about 10 carbon atoms, still more preferably from 2 to about 6 carbon atoms.
  • Especially preferred alkenyl groups have 3 carbon atoms (i.e., 1- propenyl or 2-propenyl), with the allyl moiety being particularly preferred.
  • Phenyl and naphthyl are generally preferred aryl groups.
  • Alkoxy groups include those alkoxy groups having one or more oxygen linkage and preferably have from 1 to 15 carbon atoms, more preferably from 1 to about 6 carbon atoms. Said substituted R and R.
  • alkyl groups such as alkyl groups having from 1 to 10 carbon atoms or from 1 to 6 carbon atoms
  • alkenyl groups such as alkenyl groups having from 2 to 10 carbon atoms or 2 to 6 carbon atoms
  • aryl groups having from 6 to 10 carbon atoms
  • halogen such as fluoro, chloro and bromo
  • N, O and S including heteroalkyl, e.g., heteroalkyl having one or more of said hetero atom linkages (and thus including alkoxy, aminoalkyl and thioalkyl) and from 1 to 10 carbon atoms or from 1 to 6 carbon atoms.
  • Preferred compounds of formula I include /Mapachone, 3-allyl-/?- lapachone, 3-bromo-)-Mapachone, 3-OH-/Mapachone and 3-allyl-/?- lapachone and 3-bromo- Mapachone are more preferred.
  • Preferred compounds of formula II include 3-bromo-alpha- lapacheone (compound 4 of Table 1 ).
  • This compound also causes suppression of survival, albeit at slightly higher concentrations, in human ovary and breast cells.
  • typical apoptosis was not detected in any other human cancer cells of epithelial origins including colon, kidney, lung, breast, or ovary exposed to the drug other than the prostate cells.
  • Human hematopoietic leukemia cells (HL-60) were induced to undergo either apoptosis or differentiation depending on the concentration used.
  • a suitable effective dose of one or more compounds of formulae I or II will be preferably in the range of 10 to 500,000 ⁇ g per kilogram body weight of recipient per day, more preferably in the range of 1000 to 50,000 ⁇ g per kilogram body weight per day, most preferably in the range of 5000 to 25,000 ⁇ g per kilogram body weight per day.
  • the desired dose is suitably administered once or several more sub-doses administered at appropriate intervals throughout the day, or other appropriate schedule. These sub-doses may be administered as unit dosage forms, for example, containing 1 to 20,000 ⁇ g, preferably 10 to 10,000 ⁇ g per unit dosage form.
  • the subject is a human. Still more preferably, the human has CaP.
  • Administration of the compounds of the invention may be by any suitable route including oral, rectal, nasal, topical (including buccal and sublingual) and parenteral (including subcutaneous, intramuscular, intravenous and intradermal) with oral or parenteral being preferred. It will be appreciated that the preferred route may vary with, for example, the condition and age of the recipient.
  • the administrative ingredients may be used in therapy in conjunction with other medicaments.
  • compositions of the invention comprise at least one compound of formulae I or II together with one or more acceptable carriers thereof and optionally other therapeutic ingredients, including those therapeutic agents discussed supra.
  • the carrier(s) must be "acceptable” in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • the compositions include those suitable for oral, rectal, nasal, topical (including buccal and sublingual) or parenteral (including subcutaneous, intramuscular, intravenous and intradermal) administration.
  • the compositions may conveniently be presented in unit dosage form, e.g., tablets and sustained release capsules, and in liposomes and may be prepared by any methods well known in the art of pharmacy.
  • compositions are prepared by uniformly and intimately bringing into association the active ingredients with liquid carriers, liposomes or finely divided solid carriers or both, and then if necessary shaping the product.
  • compositions of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in- water liquid emulsion or a water-in-oil liquid emulsion or packed in liposomes and as a bolus, etc.
  • a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface-active or dispersing agent.
  • Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • the tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein.
  • compositions suitable for topical administration include lozenges comprising the ingredients in a flavored basis, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the ingredient to be administered in a suitable liquid carrier.
  • compositions suitable for topical administration to the skin may be presented as ointments, creams, gels and pastes comprising one or more compounds of formulae I or II and a pharmaceutically acceptable carrier.
  • a suitable topical delivery system is a transdermal patch containing the ingredient to be administered.
  • compositions suitable for rectal administration may be presented as a suppository with a suitable base comprising, for example, cocoa butter or a salicylate.
  • compositions suitable for nasal administration wherein the carrier is a solid include a coarse powder having a particle size, for example, in the range 20 to 500 microns which is administered in the manner in which snuff is taken, i.e., by rapid inhalation through the nasal passage from a container of the powder held close up to the nose.
  • Suitable formulations wherein the carrier is a liquid, for administration, as for example, a nasal spray or as nasal drops, include aqueous or oily solutions of the active ingredient.
  • compositions suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
  • the formulations may be presented in unit-dose or multi-dose containers, for example, sealed ampules and vials, and may be stored in a freeze dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, water for injections, immediately prior to use.
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
  • the compounds are preferably dissolved in a non-ionic solubilizer such as an ethylene oxide ester-ether and fatty acid glycerides commercially available as Cremphor EL (BASF).
  • a non-ionic solubilizer such as an ethylene oxide ester-ether and fatty acid glycerides commercially available as Cremphor EL (BASF).
  • formulations of this invention may include other agents conventional in the art having regard to the type of formulation in question, for example, those suitable for oral administration may include flavoring agents.
  • /Mapachone was kindly provided by Dr. A. Matter (CIBA-GEIGY Ltd., Switzerland). It was dissolved in dimethyl sulfoxide (DMSO) at 20 mM concentration, aliquoted, and kept at -20°C.
  • DMSO dimethyl sulfoxide
  • HL-60 human promyelocytic leukemia cell line
  • MCF-7 and 21 MT human breast epithelial cell line
  • AD 2780s human ovary carcinoma
  • 293 human kidney epithelial cell line
  • SW11 16 human colon adenocarcinoma
  • human lung carcinoma cell lines H596, H520
  • Hela and Hela- bcl-2 cells (Meikrantz, W., et al., Proc. Natl. Acad. Sci. USA, 91 :3754- 3758 (1994), kindly provided by Drs. W. Meikrantz and R. Schlegel (Harvard School of Public Health, Boston, MA), were cultured in Dulbecco's modified Eagle's medium (Life Technologies, Inc.) supplemented with 10% FCS, 2 mM L-glutamine, and 800 //g/ml of G418.
  • Dulbecco's modified Eagle's medium Life Technologies, Inc.
  • Exponentially growing cells were seeded (2000 cells/dish) in 60 mm culture dishes and allowed to attach for 48 hours. B-lapachone was added in less than 5 ⁇ volume (corresponding to a final DMSO concentration of less than 0.1 %) directly to dishes from concentrated working solutions in DMSO. Control dishes received DMSO alone at equal volume. After 1 to 4 h, cells were rinsed and drug free medium was added to the cells. Cultures were observed daily for 10 to 20 days, cells were fixed and stained with modified Wright-Giemsa Stain (Sigma). Colonies of greater than 30 cells were scored as survivors.
  • Nuclear extract was prepared from exponentially growing cells (Dignam, J.D., et al., Nucleic Acids Res., 1 1 : 1475 (1983)).
  • the ECL assay system was used to detect p53 and bcl-2 levels. Briefly, nuclear protein samples (10 ⁇ g per sample) were electrophoresed in a sodium dodecyl sulfate-polyacrylamide gel and then electrophoretically transferred to a nitrocellulose membrane. The blot was blocked, washed, and incubated with p53, bcl-2, or p21 (Cip1 /Waf1 ) antibody (Oncogene Science, Cambridge, MA) at 1 : 1000 dilution.
  • the filter was then incubated with a secondary antibody that was conjugated with horseradish peroxidase. Finally, the filter was developed with detection reagents (RPN 2109:Amersham) and exposed to a hyperfilm- ECL (RPN 2103).
  • Example 1 Effects of jg-Lapachone on Survival of Human Cancer Cells
  • Human carcinoma cell lines of different histotypes were used to test the anti-survival effect of /Mapachone.
  • Androgen independent human prostate tumor cells PC-3 and DU145 were treated with ⁇ - lapachone in vitro. Cell survival was determined by colony formation assay, /Mapachone inhibits proliferation of both cell lines with an IC 100 of 4 to 8 ⁇ M ( Figure 1 ).
  • LNCaP cells were equally sensitive to ⁇ - lapachone.
  • 21 MT a human breast carcinoma cell line
  • AD2780s a human ovary carcinoma cell line
  • Apoptosis as determined by DNA laddering and chromosome condensation, was not detected in ⁇ - lapachone treated 21 -MT (human breast epithelial cell line), H520 (human lung carcinoma cell lines), SW1 1 16 (human colon adenocarcinoma), A2780s (human ovary carcinoma) cells.
  • 21 -MT human breast epithelial cell line
  • H520 human lung carcinoma cell lines
  • SW1 1 16 human colon adenocarcinoma
  • A2780s human ovary carcinoma
  • Apoptosis Induced by yff-Lapachone is Independent of Expression of p53 and bcl-2.
  • bcl-2 has been implicated in the resistance of cancer cells to chemotherapeutic drugs including prostate cells (Berchem, G.J., et al., Cancer Res. 55:735-738 (1995)).
  • chemotherapeutic drugs including prostate cells
  • bcl-2 expression was measured by Western blot assay. As shown in Fig. 3, bcl-2 expression is high in PC-3 and low in DU145 cells, which does not correlate with their sensitivity to /Mapachone induced apoptosis.
  • Hela cells with ectopic overexpression of bcl-2 (hela-bcl-2) (Meikrantz, W., et al., supra) was not significantly resistant to /Mapachone in comparison with its parental cell line (IC100 was 16 ⁇ M in parental cells, and 32 ⁇ M in Hela-bcl-2 cells) (data not shown).
  • p53 status has been shown to be important for apoptosis in cancer cells provoked by ionizing radiation and chemotherapeutic drugs (Lowe, S., et al., Science 266:807-810 (1994)).
  • p 53 was expressed in DU145 cells, but was not detectable in PC-3 cells (Fig. 3A), although apoptosis was induced in both cell lines (Fig. 2A).
  • ⁇ - lapachone treatment did not significantly induce expression of p53 (Fig. 3B).
  • /Mapachone was also tested in hematopoietic cancer cells.
  • /Mapachone was tested against human prostate tumor in nude mice.
  • a hormone refractory human prostate adenocarcinoma cell line (PC-3) was inoculated into nude mice.
  • Treatment was initiated when tumor reached 100 to 250 mm 3 . Without drug treatment (mouse 5), the tumor grew rapidly and the mouse died when the tumor reached about 400 mm 3 (Fig. 5).
  • /Mapachone given at 500 mg/kg, stopped tumor growth (mouse 2, Fig. 5). At intermediate dosage (250 mg.kg, mouse 1 and 3), /Mapachone also showed intermediate inhibition on tumor growth (Fig. 5).
  • Mouse 4 did not develop an appreciable tumor mass under the treatment with /Mapachone (500 mg/kg). No sign of drug toxicity was observed.
  • Mapachone was determined in a widely used prostate tumor model, Dunning R-3327 rat prostate adenocarcinoma.
  • Dunning R-3327 prostate adenocarcinoma cells were inoculated into Copenhagen rats. Solid tumor masses were formed one week later. Rats in the treatment group received one dose of ⁇ -lapachone at 50 mg/kg, I.p. Tumor necrosis was observed 24 hours after drug treatment in every treated rats, but not in untreated controls. Tumor volume was measured. The results are set forth in Figures 6 and 7.

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Abstract

On a découvert que des composés, correspondant aux formules (I) et (II) ci-dessous, peuvent servir à stimuler sélectivement la mort de cellules prostatiques cancéreuses de mammifères et sont donc utiles pour traiter le cancer de la prostate. Dans ces formules, R et R1 sont chacun choisis indépendamment dans le groupe consistant en hydrogène, hydroxy, thio, halogène mais aussi alkyle, alcényle, aryle et alcoxy substitués ou non, ainsi que leurs sels; la double liaison en pointillé entre les cycles carbone auxquels R et R1 sont liés représente une double liaison facultative des cycles. Des composés préférés de formule (I) incluent ceux où au moins l'un des substituants R et R1 est hydrogène et/ou au moins l'un de ces substituants est allyle. Les composés particulièrement préférés incluent β-lapachone (où R et R1 représentent donc chacun hydrogène), allyle-β-lapachone, et surtout 3-allyle-β-lapachone (R représentant donc allyle et R1 hydrogène) et 3-bromo-β-lapachone (R représentant donc bromo et R1 hydrogène).
PCT/US1996/013656 1995-08-24 1996-08-23 Agents anti-tumoraux derives de beta-lapachones Ceased WO1997008162A1 (fr)

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AU69012/96A AU6901296A (en) 1995-08-24 1996-08-23 Beta-lapachone derivatives as antitumor agents
US09/028,400 US6245807B1 (en) 1995-08-24 1998-02-24 Treatment of human prostate disease

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US282895P 1995-08-24 1995-08-24
US60/002,828 1995-08-24

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WO2000066528A3 (fr) * 1999-04-30 2001-02-08 Slil Biomedical Corp Novel quinones utilisees dans le traitements de maladies
US6482943B1 (en) 1999-04-30 2002-11-19 Slil Biomedical Corporation Quinones as disease therapies
WO2003090710A1 (fr) * 2002-04-23 2003-11-06 Case Western Reserve University Systemes d'administration de lapachone, compositions de lapachone et utilisations associees
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EP1420777A4 (fr) * 2001-07-31 2009-03-04 Arqule Inc Compositions pharmaceutiques contenant beta-lapachone ou des derives ou des analogues correspondants, et leurs methodes d'utilisation
EP2137168A4 (fr) * 2007-03-16 2012-06-27 Lankenau Inst Medical Res Nouveaux inhibiteurs ido et leurs procédés d'utilisation
CN105503692A (zh) * 2015-12-27 2016-04-20 新乡医学院 一种α-拉帕醇类似物及其合成方法和作为抗肿瘤药物的应用
WO2019050422A1 (fr) * 2017-09-08 2019-03-14 Instituto De Medicina Molecular Antagonistes de 5-lipoxygénase

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