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WO2001030341A1 - Inhibiteurs de l'expression de la cyclo-oxygenase-2 - Google Patents

Inhibiteurs de l'expression de la cyclo-oxygenase-2 Download PDF

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Publication number
WO2001030341A1
WO2001030341A1 PCT/JP2000/007462 JP0007462W WO0130341A1 WO 2001030341 A1 WO2001030341 A1 WO 2001030341A1 JP 0007462 W JP0007462 W JP 0007462W WO 0130341 A1 WO0130341 A1 WO 0130341A1
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Prior art keywords
group
expression
cyclooxygenase
expression inhibitor
hydroxyl group
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Ceased
Application number
PCT/JP2000/007462
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English (en)
Japanese (ja)
Inventor
Keiji Wakabayashi
Hajime Komatsu
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
ORGANIZATION FOR PHARMACEUTICAL SAFETY AND RESEARCH
National Cancer Center Japan
Original Assignee
ORGANIZATION FOR PHARMACEUTICAL SAFETY AND RESEARCH
National Cancer Center Japan
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Priority to AU79570/00A priority Critical patent/AU7957000A/en
Publication of WO2001030341A1 publication Critical patent/WO2001030341A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/12—Ketones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to a cyclooxygenase-2 expression inhibitor useful for preventing cancer and alleviating inflammatory symptoms.
  • Non-steroidal anti-inflammatory drugs are widely used as anti-inflammatory drugs and analgesics. NSAIDs are said to exhibit anti-inflammatory effects through inhibition of the enzymatic activity of prostaglandin synthase cyclooxygenase (hereinafter abbreviated as C0X). Inflammatory chemical mediators such as prostaglandin E2 are synthesized by the action of C0X using arachidonic acid as a substrate. It is known that C0X has the products of different genes, C0X-1 and C0X-2. C0X-1 is widely expressed in digestive organs, whereas C0X-2 is induced locally in inflammatory lesions. Cytokine (J. Biol. Chem.
  • drugs that can selectively inhibit the expression of C0X-2 itself, as well as activity inhibitors are useful as anti-inflammatory agents with few side effects as well as C0X-2 selective activity inhibitors. Conceivable.
  • reports on compounds that suppress the expression of C0X-2 There are few reports.
  • the present inventors have established a method for screening a C0X-2 transcription repressor active substance using colon cancer cells transformed with a vector in which a reporter gene is arranged downstream of the C0X-2 promoter ( J. Ethnopharmacology, 66: 227-233, 199 9).
  • only berberine is the only compound whose transcription inhibitory activity of C0X-2 has been confirmed by this method. Therefore, it is currently difficult to identify the basic structure required for C0X-2 selective inhibitors. Identifying the basic structure and accumulating information on the substituents involved in the expression-suppressing action are essential for enhancing the efficacy as a drug.
  • flavonoids are known to contain compounds that have antiallergic, antiinflammatory, antiviral, antiproliferative, or anticancer effects.
  • a basic structure effective for suppressing the expression of C0X-2 cannot be specified.
  • An object of the present invention is to clarify the basic structure necessary for suppressing the expression of C0X-2 and to provide a drug effective for suppressing the expression of C0X-2.
  • the present inventors have already described a method using a human colon cancer cell line into which a reporter gene has been introduced (j. Ethnopharmacology, 1999, 66: 227-233) as a method for screening a compound having an activity of suppressing the expression of C0X-2.
  • colon cancer cells transformed with a vector in which a gene encoding /?-Galactosidase is linked downstream of the C0X-2 promoter are used.
  • the effect of the test compound on the expression level of C0X-2 can be evaluated in vitro as galactosidase activity.
  • the present inventors evaluated the inhibitory action of the C0X-2 gene on several compounds including flavonoids by this screening method, and analyzed the relationship between the magnitude of the activity and the structure of the test compound. Then, they found the basic structure necessary for the action of suppressing the expression of the C0X-2 gene, and clarified the structural features affecting the action, thereby completing the present invention. That is, the present invention relates to the following C0X-2 expression inhibitor.
  • a C0X-2 expression inhibitor comprising a dihydroxyacetophenone derivative represented by the following general formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.
  • XI and X2 are simultaneously or independently a hydrogen atom, or a halogen
  • R1 is a hydrogen atom or a hydroxyl group
  • R2 is an alkyl group or a substituted alkyl group
  • R3 represents a hydrogen atom, a hydroxyl group, an oxyalkyl group, or an oxyalkyl group or a hydroxyl group which may form a ring with the alkyl group or the substituted alkyl group of R2, and R4 represents a hydroxyl group or an oxyalkyl group;
  • Rl, R3, and R4 is a hydroxyl group
  • a prophylactic agent for a tumor overexpressing C0X-2 comprising the C0X-2 expression inhibitor according to [1].
  • the present invention relates to use of the compound represented by the general formula (1) in the production of a C0X-2 expression inhibitor. Further, the present invention relates to a method for preventing a tumor overexpressing C0X-2, which comprises a step of administering the compound represented by the general formula (1).
  • the compound used as an active ingredient in the C0X-2 expression inhibitor of the present invention is a dihydroxyacetophenone derivative represented by the general formula (1) or a pharmaceutically acceptable salt thereof.
  • the present inventors have found that the structure represented by the general formula (1) is a structure necessary for maintaining the inhibitory activity of C0X-2, and furthermore, structural features closely related to the action thereof. Revealed.
  • the following three conditions are effective for enhancing the effect of suppressing the expression of C0X-2 by the compound of the present invention.
  • the expression suppression of C0X-2 means an action of inhibiting any step of the transcription and translation processes of the C0X-2 gene.
  • halogen is selected from any halogen atom represented by F, Cl, Br, and I.
  • the alkyl group is selected from a lower alkyl group such as a methyl group and an ethyl group, or an aromatic alkyl group such as a benzyl group and a phenethyl group. These alkyl groups are It may be substituted with a hydroxyl group, halogen, or the like.
  • examples of the alkyl group for R2 include benzyl, phenethyl, methyl, ethyl, propyl, and isopropyl.
  • examples of the substituted alkyl group for R2 include bromomethyldimethoxymethyl and the like.
  • the alkyl group or substituted alkyl group of R2 can also form a ring (C ⁇ ) with the hydroxyl group or oxyalkyl group of R3.
  • R2 is a phenethyl group, by forming a ring with the hydroxyl group of R3, a chromone nucleus (chromone) is formed and becomes a flavone.
  • XI and X2 may be, simultaneously or independently, a hydrogen atom or a halogen.
  • a hydroxyl group is present at the 2-position (Rl) and 4-position (R4) of the ring A, it is desirable that the 3-position (X2) and the 5-position (XI) are simultaneously substituted with halogen.
  • XI and X2 are Br simultaneously, a high level of C0X-2 expression inhibitory activity can be achieved.
  • the compound represented by the general formula (1) can be obtained by a known method.
  • a group of compounds having a benzene group or a phenethyl group in which a benzene ring is substituted with one or two hydroxyl groups (-0H) as R2 are compounds called flavonoids.
  • Flavonoids report compounds having various structures derived from many plants, and a compound having the structure given by the general formula (1) can be selected from the compounds. Many of the compounds required for the C0X-2 expression inhibitor of the present invention are on the market. In particular, compounds belonging to flavonoids are easily available. Methods for chemically synthesizing these compounds are also known.
  • flavonoid compounds whose structures are known.
  • the anticancer and anti-inflammatory effects of these flavonoids are based on the inhibition of C0X-2.
  • luteolin has a carcinogenic effect Is known, but the mechanism is unknown (Cancer Letters, 1994, 8
  • resacetophenone is also known in its structure, it is a novel finding that it has a C0X-2 expression inhibitory action. Furthermore, 3,5-dibromo-2,4-dihydroxyacetophenone is a known compound used for a reagent for analyzing heavy metals (J. Sci. Ind. Res., 1983, 18: 66-75, J. Sci. Inst. Chem. India, 1984, 56: 163-164) 0 However, it is not known to have any effect of suppressing the expression of COX-2.
  • the agent for suppressing the expression of C0X-2 according to the present invention is useful for preventing or treating diseases associated with abnormal expression of C0X-2. Specifically, it can be used for preventing general tumors overexpressing C0X-2 such as colorectal cancer, or for alleviating inflammatory symptoms. It has already been described that the expression of C0X-2 is enhanced in colorectal cancer (Cancer Res. 1995, 55: 2556-2559, Cancer Res. 1995, 55: 3785-3789). It has been pointed out that suppression of COX-2 expression may lead to prevention of cancer. Therefore, the C0X-2 expression inhibitor is useful as a chemical preventive for colorectal cancer. Excess of C0X-2 not only in colorectal cancer but also in gastric cancer (Cancer Res.
  • the cancer preventive agent of the present invention is also effective against these cancers. Since the C0X-2 expression inhibitor according to the present invention controls the expression of C0X-2, it can achieve higher selectivity than the activity inhibitor. Because C0X-2 and COX-1 are products of different genes, it is unlikely that a compound that regulates the expression of one will be involved in the expression of the other. Activity It is difficult for inhibitors to selectively inhibit different enzymes having similar activities.
  • the compound that has been found to exhibit C0X-2 expression inhibitory activity can be used alone or in combination with a plurality of compounds to form a pharmaceutical preparation using a known formulation technique. That is, a pharmaceutical preparation can be obtained by mixing these compounds with a pharmaceutically acceptable excipient.
  • the compounds of the present invention can be administered to animals and humans as they are or together with conventional pharmaceutical carriers.
  • the administration form is not particularly limited, and is appropriately selected and used as needed. Specific examples include oral preparations such as tablets, capsules, granules, fine granules and powders, and parenteral preparations such as injections and suppositories.
  • Oral preparations are manufactured according to a conventional method using excipients such as starch, lactose, sucrose, mannitol, carboxymethylcellulose, corn starch, and inorganic salts.
  • excipients such as starch, lactose, sucrose, mannitol, carboxymethylcellulose, corn starch, and inorganic salts.
  • binders, disintegrants, surfactants, lubricants, fluidity promoters, flavoring agents, coloring agents, fragrances, and the like can be used.
  • the compounds of the present invention can also be administered as suspensions, emulsions, syrups, and elixirs. These various forms may contain flavoring agents and coloring agents.
  • Parenteral preparations are manufactured according to standard methods, and generally use distilled water for injection, physiological saline, aqueous glucose solution, vegetable oil for injection, sesame oil, laccase oil, soybean oil, corn oil, propylene glycol, polyethylene glycol, etc. be able to. If necessary, bactericides, preservatives and stabilizers may be added.
  • Other parenteral preparations include liquid preparations for external use, ointments such as ointments, suppositories for rectal administration, and the like, and are produced according to a conventional method.
  • the content of the active ingredient in the C0X-2 expression inhibitor according to the present invention can be appropriately adjusted so that the required dose can be given according to the selected administration route.
  • the usual dosage is 0.0 1 // g ⁇ l mg / kg body weight, Desirably, it can represent 0.01 g to 0.1 mg, more preferably 0.1 l / g to 0.01 mg.
  • the final dose is appropriately adjusted in consideration of the patient's weight, age, sex, symptoms, etc., as a whole.
  • FIG. 1 is a graph showing the effects of resacetophenone and BHAP on the administration-dependent inhibition of the C0X-2 promoter overnight transcription activity.
  • the horizontal axis represents the concentration of each compound, and the vertical axis represents the C0X-2 promoter transcription activity.
  • the bar on the graph represents SD.
  • c Elio was purchased from diethylene Cu Chi All (eriodictyol ), Fisetin, kae mpherol, noreteolin (luteolin), and rhamnetin (rhamnetin) (extra Extrasynthese (Genay, France)).
  • Genistein was purchased from Fujicco. Phloretine, quercetin, and resacetophenone were purchased from Wako Pure Chemical.
  • Evigallocatechin (epigal locatechin) was purchased from Kurita Water Industries Ltd.
  • DLD-1 a human colon adenocarcinoma cell line
  • RPMI 1640 medium supplemented with 5% heat-treated inactivated fetal calf serum (Hyclone Laboratories, Inc., Logan, UT) and antibiotics (100 / g / ml streptomycin and 100 units / ml penicillin). In, 37. It was maintained at C, 5% 0 2.
  • Cells (2.0 ⁇ 10 5 cells / ml) were plated on 96-well tissue culture plates and pre-cultured for 24 hours. Thereafter, the cells were treated with the test compound.
  • the cell viability of each culture was determined using 3- (4,5-dimethylthiazol-2-yl) -2,5-diphenylenotetrazolium bromide (MTT) Atsui (Mosmann, T. Rapid colorimetoric assay for cellular growth and suvival: determined by Application to prolireration and cytotoxicity assays. J. Immunol. Methods. 65: 55-63, 1983).
  • MTT 3- (4,5-dimethylthiazol-2-yl) -2,5-diphenylenotetrazolium bromide
  • PCR primer 1 forward primer 1; 5, -GGAACTCTTCACTCTATC CTGCTATATAAGGTGA -3 '; SEQ ID NO: 1 corresponding to the sequence at the 5' end of the -2046 to +32 regions, which is the 5 'region of the human C0X-2 gene.
  • PCR primer antisense primer; 5'-TCCTGACGCTCACTGCAATGCGTATGACAATT
  • DLD-1 cells were transformed with PC0X2 / B2-5Gas BSD plasmid DNA.
  • 2 ⁇ 10 6 DLD-1 cells were grown in 10 cm culture dishes. After overnight attachment, cells were transformed with 15 m of plasmid DNA using TfxTM-20 (Promega Corporation, Madison, Wis.) According to the manufacturer's manual.
  • Stable transformed cells were selected on medium containing 20 mg / ml blasticidin S hydrochloride (Kaken Pharmaceutical Co. Ltd).
  • the stable transformed cells having PC0X2 / B2-? Gal-BSD in the genomic DNA of DLD-1 cells were named DLD-1 / C0X-2 / B2-5Gal-BSD.
  • Gat BSD cell genotype is a population with a genotype, and the genomic DNA obtained by limiting dilution contains 2078 b of C0X-2 promoter and lacZ. A subclone containing a normal DNA fragment downstream of the gene was used for the experiment.
  • the cells were inoculated into a 96-well micro-tie plate at a density of 2 ⁇ 10 4 cells per well and pre-cultured for 24 hours. Next, the cells were treated with the test compound, and the total 3-galactosidase activity of the DLD-1 cells in each well was measured by colorimetry using 0-nitrophenyl-D-galactoviranoside (0NPG). Measured by Atsushi. The standard for DLD-1 cells /?-Galactosidase activity was measured in DLD-l / C0X-2 / B2-? Gat BSD cells not treated with the test compound as a control, and the value was set to 0. Set.
  • the 3-galactosidase activity of DLD-1 / C0X-2 / B2-? Gal-BSD treated with TGF was set as 100%.
  • the percentage of? -Galactosidase activity when treated with each test compound was calculated from the three wells.
  • Flaponol Eri if'octyl 12.3 ⁇ 0.4 88.8 Flapanone Luteolin 12.7 ⁇ 0.4 99.2 Flapon
  • Flaponol ke 7 erol 24.3 ⁇ 2. 94.7 Flaponol phloretin 34.7 ⁇ 3.4 73.6 Dihydrochalcone Weak catechin 144.1 ⁇ 25.4 78.8 Flavanol
  • the inhibitory effects could be divided into three groups: strong, weak and no inhibitory.
  • flavonol was a strong suppressor of the C0X-2 promoter overnight.
  • flavanols with the exception of epigallocatechin, were weakly sub-lessers of the C0X-2 promoter.
  • Eriodictyol belonging to flavanone, genistein belonging to isoflavone and phloretine belonging to dihydrochalcone all have a 4-oxo group on the C ring (see X), and C0X-2 It was a strong sub-lesser of the promoter.
  • BHAP suppressed COX-2 promoted transcriptional activity in a dose-dependent manner (Fig. 2).
  • BHAP was found to inhibit C0X-2 promoter overnight transcriptional activity 10-fold more than resacetophenone, which has a higher oxygen electron density than BHAP (Table 3).
  • the compound represented by the general formula (1) is expected to be a C0X-2 expression inhibitor.
  • the present invention provides a novel C0X-2 expression inhibitor.
  • the C0X-2 expression inhibitor provided by the present invention has a low toxicity and a simple structure, and is useful for drug discovery in the future.
  • the prophylactic agent for a tumor overexpressing C0X-2 comprising the C0X-2 expression inhibitor of the present invention can be expected as a drug with excellent selectivity. In other words, since it acts on the expression of C0X-2, which is encoded by a different gene from C0X-1, it does not theoretically affect the activity of C0X-1 and has side effects such as gastrointestinal disorders. It can be an unaccompanied drug.
  • the structure of a compound necessary for suppressing the expression of C0X-2 has been clarified.
  • the relationship between the inhibitory effect of C0X-2 expression and the structure of a compound, which is extremely important information in drug development, has not been accumulated at all in the past.
  • the present invention is closely related to the C0X-2 expression-suppressing action, in which the substitution of the hydroxyl group in the A ring of the dihydroxyacetophenone derivative with a halogen, and the substitution of R2 by a benzyl group in which the benzene ring is substituted with a hydroxyl group. For the first time.

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Abstract

L'invention concerne des inhibiteurs de l'expression de la COX-2 contenant, en tant qu'ingrédient actif, des dérivés de dihydroxyacétophénone représentés par la formule générale (1). Ces inhibiteurs de l'expression de la COX-2 sont utiles dans la prévention des cancers associés à la surexpression de la COX-2, tels que le cancer du côlon.
PCT/JP2000/007462 1999-10-25 2000-10-25 Inhibiteurs de l'expression de la cyclo-oxygenase-2 Ceased WO2001030341A1 (fr)

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AU79570/00A AU7957000A (en) 1999-10-25 2000-10-25 Cyclooxygenase-2 expression inhibitors

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JP11/302979 1999-10-25
JP30297999 1999-10-25

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2003002811A (ja) * 2001-11-07 2003-01-08 Naris Cosmetics Co Ltd ＩｇＥ産生抑制剤
WO2005000778A1 (fr) * 2003-06-27 2005-01-06 Kyowa Hakko Kogyo Co., Ltd. Inhibiteur de proteines de la famille hsp90
JP2005521715A (ja) * 2002-03-22 2005-07-21 ユニゲン・ファーマシューティカルス・インコーポレーテッド 二重ｃｏｘ−２および５−リポキシゲナーゼ阻害剤のアカシアからの単離
US8535735B2 (en) 2002-03-01 2013-09-17 Unigen, Inc. Identification of free-B-ring flavonoids as potent COX-2 inhibitors
US8652535B2 (en) 2002-04-30 2014-02-18 Unigen, Inc. Formulation of a mixture of free-B-ring flavonoids and flavans for use in the prevention and treatment of cognitive decline and age-related memory impairments
US8771761B2 (en) 2006-10-12 2014-07-08 Unigen, Inc. Composition for treating atopic dermatitis comprising extracts of bamboo and scutellaria
US8790724B2 (en) 2003-04-04 2014-07-29 Unigen, Inc. Formulation of dual cycloxygenase (COX) and lipoxygenase (LOX) inhibitors for mammal skin care
US9655940B2 (en) 2002-04-30 2017-05-23 Unigen, Inc. Formulation of a mixture of free-B-ring flavonoids and flavans as a therapeutic agent

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LIANG YU-CHIH ET AL.: "Suppression of inducible cyclooxygenase and inducible nitric oxide synthase by apigenin and related flavonoids in mouse macrophages", CARCINOGENESIS, vol. 20, no. 10, October 1999 (1999-10-01), pages 1945 - 1952, XP002936369 *
MUTOH MICHIHIRO ET AL.: "Suppression of cyclooxygenase-2 promoter-dependent transcriptional activity in colon cancer cells by chemopreventive agents with a resorcin-type structure", CARCINOGENESIS, vol. 21, no. 5, 2000, pages 959 - 963, XP002936370 *

Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2003002811A (ja) * 2001-11-07 2003-01-08 Naris Cosmetics Co Ltd ＩｇＥ産生抑制剤
US9061039B2 (en) 2002-03-01 2015-06-23 Unigen, Inc. Identification of Free-B-Ring flavonoids as potent COX-2 inhibitors
US8535735B2 (en) 2002-03-01 2013-09-17 Unigen, Inc. Identification of free-B-ring flavonoids as potent COX-2 inhibitors
US8568799B2 (en) 2002-03-22 2013-10-29 Unigen, Inc. Isolation of a dual COX-2 and 5-lipoxygenase inhibitor from acacia
US9168242B2 (en) 2002-03-22 2015-10-27 Unigen, Inc. Isolation of a dual COX-2 and 5-lipdxygenase inhibitor from Acacia
JP2005521715A (ja) * 2002-03-22 2005-07-21 ユニゲン・ファーマシューティカルス・インコーポレーテッド 二重ｃｏｘ−２および５−リポキシゲナーゼ阻害剤のアカシアからの単離
US8124134B2 (en) 2002-03-22 2012-02-28 Unigen, Inc. Isolation of a dual COX-2 and 5-lipoxygenase inhibitor from Acacia
US8652535B2 (en) 2002-04-30 2014-02-18 Unigen, Inc. Formulation of a mixture of free-B-ring flavonoids and flavans for use in the prevention and treatment of cognitive decline and age-related memory impairments
US9655940B2 (en) 2002-04-30 2017-05-23 Unigen, Inc. Formulation of a mixture of free-B-ring flavonoids and flavans as a therapeutic agent
US9849152B2 (en) 2002-04-30 2017-12-26 Unigen, Inc. Formulation of a mixture of Free-B-ring flavonoids and flavans as a therapeutic agent
US8790724B2 (en) 2003-04-04 2014-07-29 Unigen, Inc. Formulation of dual cycloxygenase (COX) and lipoxygenase (LOX) inhibitors for mammal skin care
US9622964B2 (en) 2003-04-04 2017-04-18 Unigen, Inc. Formulation of dual cycloxygenase (COX) and lipoxygenase (LOX) inhibitors for mammal skin care
US7767693B2 (en) 2003-06-27 2010-08-03 Kyowa Hakko Kirin Co., Ltd. Hsp90 family protein inhibitors
US7538224B2 (en) 2003-06-27 2009-05-26 Kyowa Hakko Kogyo Co., Ltd. Hsp90 family protein inhibitors
WO2005000778A1 (fr) * 2003-06-27 2005-01-06 Kyowa Hakko Kogyo Co., Ltd. Inhibiteur de proteines de la famille hsp90
US8771761B2 (en) 2006-10-12 2014-07-08 Unigen, Inc. Composition for treating atopic dermatitis comprising extracts of bamboo and scutellaria

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