Bifunctional antagonists of cytokine-sensitive protein kinase activation cascades and methods for use as anti-inflammatory agents

摘要

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.