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 inflammatoryresponses associated with TNF-.alpha. and fibroblast proliferation in vivo andin vitro by blocking activation of both the c-Jun and p38 kinases. Thecompounds of the invention possess greater than additive activity as comparedto the individual constituents of each compound. One such constituent blocksactivation of c-Jun kinase while the other blocks activation of p38 kinase, ina non-overlapping manner. The compounds of the invention neither appreciablyinhibit the activity of cAMP phosphodiesterase nor the hydrolysis ofphosphatidic acid, and are neither cytotoxic nor cytostatic. Methods for theuse of the novel compounds as anti-imflammatory agents are also described. Themethods are expected to be of use in reducing or protecting a vertebrate hostagainst inflammatory responses (for example, after angioplasty), in limitingfibrosis (for example, of the liver in cirrhosis), in inhibiting cellsenescence, cell apoptosis and UV induced cutaneous immune suppression.