Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
2000-07-21
2002-08-20
Riley, Jezia (Department: 1656)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C514S001000, C514S023000, C514S054000, C514S061000, C536S123000, C536S123100, C536S123130
Reexamination Certificate
active
06436911
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to an interleukin-12 (IL-12) production inhibitor and a keratan sulfate oligosaccharide derivative useful as an active ingredient of the IL-12 production inhibitor.
IL-12 is a cytokine composed of 70 kDa glycoprotein (p70) which is composed of linked two polypeptide chains of 35 kDa and 40 kDa and is known to play a pivotal role in the regulation of immune functions in living bodies (Shimpei Kasakura Ed., “Cytokine”, Second Edition, Revised New Edition, pp. 207-225, Nihon Igakukan, Jun. 29, 1997).
It is also known that IL-12 induces differentiation of helper T cell type-1 subset (Th1) among T cells and hence accelerates progress of pathological conditions in autoimmune diseases associated with Th1 activation.
SUMMARY OF THE INVENTION
An object of the present invention is to provide an IL-12 production inhibitor that can effectively inhibit IL-12 production.
Another object of the present invention is to provide an active ingredient of the IL-12 production inhibitor.
The present inventors found that keratan sulfate oligosaccharides and derivatives thereof had an action to inhibit IL-12 production and thus accomplished the present invention.
The present invention provides an IL-12 production inhibitor (hereafter also referred to as the inhibitor of the present invention) which comprises a keratan sulfate oligosaccharide or a derivative thereof as an active ingredient.
The keratan sulfate oligosaccharide used in the inhibitor of the present invention preferably comprises at least one repeating unit of either one of the disaccharides represented by the following formulas:
Gal(6S)-GlcNAc(6S) and Gal(6S)-GlcNAc
wherein, Gal represents a galactose residue, GlcNAc represents an N-acetylglucosamine residue, 6S indicates that 6-O-sulfate ester is formed at a hydroxyl group at the 6-position, and - represents a glycosidic linkage.
More preferably, the keratan sulfate oligosaccharide is selected from those represented by the formulas (1) to (3):
Gal(6S)&bgr;1-4GlcNAc(6S)&bgr;1-3Gal(6S)&bgr;1-4GlcNAc(6S) (1)
Gal(6S)&bgr;1-4GlcNAc(6S) (2)
Gal(6S)&bgr;1-4GlcNAc (3)
wherein, Gal represents a galactose residue, GlcNAc represents an N-acetylglucosamine residue, 6S indicates that 6-O-sulfate ester is formed at a hydroxyl group at the 6-position, &bgr;1-4 represents a &bgr;-1,4-glycosidic linkage and &bgr;1-3 represents a &bgr;-1,3-glycosidic linkage.
The keratan sulfate oligosaccharide derivative used in the inhibitor of the present invention is preferably an acyl ester at a hydroxyl group of a keratan sulfate oligosaccharide, more preferably represented by the formula (4):
wherein, X
1
to X
5
each independently represent a hydrogen atom or an acyl group, provided that at least one of X
1
to X
5
is an acyl group; Y is a hydrogen atom or SO
3
M; M is independently a hydrogen atom, or a monovalent to trivalent metal or a monovalent to trivalent base that may be ionized; the linkage represented by a wavy line represents a linkage in &agr;-glycoside configuration or &bgr;-glycoside configuration.
Preferably, in the formula (4), each of X
1
to X
5
represents an acyl group having 1 to 10 carbon atoms and M is an alkali metal.
The present invention also provides a keratan sulfate oligosaccharide derivative represented by the above formula (4) (hereafter also referred to as the derivative of the present invention).
In the derivative of the present invention, it is preferred that each of X
1
to X
5
represents an acyl group having 1 to 10 carbon atoms and M is an alkali metal in the formula (4).
Furthermore, the present invention provide a pharmaceutical composition for inhibiting IL-12 production, comprising a keratan sulfate oligosaccharide or a derivative thereof and a pharmaceutically acceptable carrier. In addition, the present invention provide a method for inhibiting IL-12 production, comprising administering an effective amount of a keratan sulfate oligosaccharide or a derivative thereof to a subject in need of inhibition of IL-12 production, and a use of a keratan sulfate oligosaccharide or a derivative thereof for manufacture of a medicament for inhibiting IL-12 production.
The IL-12 production inhibitor is useful as a reagent for investigating the roles of IL-12 in the regulation of immune functions in living bodies. It can also be used as a therapeutic or prophylactic drug for diseases of which pathological conditions are accelerated by IL-12. The IL-12 production inhibitor of the present invention is highly safe because substances derived from nature are used as its material.
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Gavin M. Brown, et al., Oligosaccharides Derived from Bovine Articular Cartilage Keratan Sulfates after Keratanase II Digestion: Implications for Keratan Sulfate Structural Fingerprinting, Biochemistry, vol. 3, No. 16, 1994 pp. 4836-4846.
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J. Drulović, et al. Serum interleukin-12 levels in patients with multiple sclerosis, Neuroscience Letters 251 (1998) 129-132.
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Asari Akira
Kurihara Hitoshi
Minamisawa Toshikazu
Miyauchi Satoshi
Xu Heping
Knobbe Martens Olson and Bear LLP
Riley Jezia
Seikagaku Corporation
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