Mapkap kinase 2-inhibitors and the use thereof in...

Details Mapkap kinase 2-inhibitors and the use thereof in... Mapkap kinase 2-inhibitors and the use thereof in...

2000-11-15

2004-01-27

Lacourciere, Karen (Department: 1635)

Organic compounds -- part of the class 532-570 series

Organic compounds

Carbohydrates or derivatives

C536S024300, C536S024310, C536S024330, C514S04400A, C435S006120

Reexamination Certificate

active

06683172

ABSTRACT:

BACKGROUND OF THE INVENTION
The invention relates to MAPKAP kinase 2 inhibitors and the use thereof in anti-inflammatory therapy. Fields of application of the invention are medicine and pharmaceutical industry.
A big part of all diseases is connected with inflammatory processes which result in the fact that the causes of the diseases are recognized and eliminated. The early response to an inflammation, e.g. as a reaction to bacterial lipopolysaccharides (LPS), results in the expression and release of pro-inflammatory and inflammatory cytokines and thus to massive inflammatory processes and to phenomena such as e.g. sepsis. Among the pro-inflammatory cytokines the tumor-necrosis factor &agr; (TCF&agr;) and interleukin-1(Il-1) stimulating, on their turn, the synthesis of further inflammatory cytokines play a central part.
Attempts have been already made to affect the course of inflammatory processes, e.g., substance S3203580 (4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl-5-(4-pyridyl)-imidazole) was describe as an efficient inhibitor of cytokine biosynthesis. Its effect is based on the inhibition of protein kinase p38 MAP kinase activated by stress (also referred to as p38 reactivating kinase, P38&agr;, p38&bgr;, CSBP-cytokine suppressive anti-inflammatory drug binding protein (J. C. Lee et al., Nature 372, 739-46 (1994)). SB203580 may as a reaction to LPS administration efficiently inhibit, at the same time, inhibiting the biosynthesis of Il-1 and TNF&agr;. The mechanism of stimulating the cytokine biosynthesis by p38 MAP kinase has so far only been understood incompletely. Various transcription factors and protein kinases were identified a substrate of p38 MAP kinase.
These downstream components of signal transmission by p38 MAPK could individually or jointly participate in the inflammatory response.
To sum up we may state that in spite of progress having undoubtedly been made in findings a possibility to affect the process of inflammation purposefully has not yet been found.
SUMMARY OF THE INVENTION
That is why the invention is based on the task to make available a new agent based on a new principle of action which may be used as anti-inflammatory therapeutic agent with possibly small side effects.
There was found that—to our surprise—only one enzyme from the spectrum of the numerous participating enzymes plays a central part in the inflammatory response—the enzymes MAPKAP kinase 2. From this the possibility is derived to use MAPKAP kinase 2 as an ideal target for the anti-inflammatory therapy.


REFERENCES:
K Miyazawa et al., Journal of Biological Chemistry, “Regulation of Interleukin-1B-induced Interleukin-6 Gene Expression in Human Fibroblast-like Synoviocytes by p38 Mitogen-activated Protein kinase,”1998, vol. 278, No. 38, pp. 24832-24838.*
Y-L Zu et al., Blood, “Activation of MAP Kinase-Activated Protein Kinase 2 in Human Neutrophils After Phorbol Ester or fMLP Peptide Stimulation,” Jun. 1996, vol. 87, No. 12,pp. 5287-5296.*
AM Badger et al.,Journal of Pharmacology and Experimental Therapeutics,“Pharmacological Profile of SB 203580, . . . Protein/p38 kinase, in Animal Models of Arthritis, Bone Resorption, Endotoxin Shock and Immune Function,” 1996,Vol,279, No. 3, pp. 1453-1461.*
K-Y Jen et al., Stem Cells,“Suppression of Gene Expression by Targeted Disruption of Messenger RNA: Available Options and Current Strategies,”2000, 18:307-319.*
DW0 Green et al., American Colllege of Surgeons,“ Antisense Oligonucleotides:An Evolving Technology for the Modulation of Gene Expression in Human Disease,” Jul. 2000, vol. 191, No. 1, pp. 93-105.*
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John C. Lee et al.; A Protein Kinase Involved in the Regulation of Inflammatory Cytokine Biosynthesis; Nature, vol. 372, Dec. 22/29, 1994; pp. 739-746.

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