C - Chemistry – Metallurgy – 07 – D
Patent
C - Chemistry, Metallurgy
07
D
C07D 475/02 (2006.01) A61K 31/505 (2006.01) A61K 31/52 (2006.01) C07D 217/24 (2006.01) C07D 239/00 (2006.01) C07D 239/96 (2006.01) C07D 285/00 (2006.01) C07D 401/14 (2006.01) C07D 473/04 (2006.01) C07D 513/04 (2006.01)
Patent
CA 2335595
Bifunctional activation cascade antagonist compounds inhibit inflammatory responses associated with TNF-.alpha. and fibroblast proliferation in vivo and in vitro by blocking activation of both the c-Jun and p38 kinases. The compounds of the invention possess greater than additive activity as compared to the individual constituents of each compound. One such constituent blocks activation of c-Jun kinase while the other blocks activation of p38 kinase, in a non-overlapping manner. The compounds of the invention neither appreciably inhibit the activity of cAMP phosphodiesterase nor the hydrolysis of phosphatidic acid, and are neither cytotoxic nor cytostatic. Methods for the use of the novel compounds as anti-imflammatory agents are also described. The methods are expected to be of use in reducing or protecting a vertebrate host against inflammatory responses (for example, after angioplasty), in limiting fibrosis (for example, of the liver in cirrhosis), in inhibiting cell senescence, cell apoptosis and UV induced cutaneous immune suppression.
L'invention concerne des composés antagonistes bifonctionnels de certaines cascades d'activation, qui inhibent les réponses inflammatoires associées au TNF-.alpha. et la prolifération des fibroblastes in vivo et in vitro en bloquant l'activation des kinases c-Jun et p38. Les composés de l'invention possèdent davantage qu'une activité additionnelle par rapport aux différents constituants de chaque composé. Un de ces constituants bloque l'activation de la kinase c-Jun, tandis que l'autre bloque l'activation de la kinase p38, sans que ces activités se chevauchent. Les composés de l'invention n'inhibent de manière appréciable ni l'activité de l'AMPc phosphodiestérase, ni l'hydrolyse de l'acide phosphatidique, et ils ne sont ni cytotoxiques ni cytostatiques. L'invention concerne également des techniques qui permettent d'utiliser ces nouveaux composés comme anti-inflammatoires. Ces techniques sont censées protéger un vertébré hôte des réponses inflammatoires (par exemple après angioplastie) ou atténuer chez lui lesdites réactions, limiter la fibrose (par exemple dans la cirrhose du foie), et inhiber la sénescence cellulaire, l'apoptose cellulaire et l'immunosuppression cutanée induite par les ultraviolets.
Carson Dennis A.
Chao Qi
Cottom Howard B.
Smart & Biggar
The Regents Of The University Of California
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