2,4,6-trimethyl-1,4-dihydro-pyridine-3,5-dicarboxylic acid esters as neuroprotective drugs

This invention pertains to a series of new derivatives of 2,4,6-trimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid, their synthesis, and the use of these compounds as platelet-activating factor antagonists, inhibitors of certain protein kinases, transcriptional inhibitors of COX-2 expression, and as agents effective in protecting brain tissue from injuries related to trauma or disease. A new series of derivatives of 2,4,6-trimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid and their synthesis have been discovered. Surprisingly, by modifying the substituent of the 3-carboxylic acid group, new compounds were produced with high activity as PAF receptor antagonists. These compounds were shown to protect neurons from brain damage that normally occurs in response to stroke and other cerebrovascular diseases. These compounds are also protective against edema generation resulting from traumatic breakdown of the blood-brain barrier. Moreover, these compounds were found to be non-toxic and cytoprotective of cells undergoing oxidative stress that would normally trigger apoptotic cell death; and to have activity as (a) antagonists of an intracellular platelet activating factor ("PAF")-binding site, (b) inhibitors of PAF- and cytokine-mediated c-aminoterminal jun kinase (JNK) and extracellular regulated kinase (ERK), and (c) transcriptional inhibitors of COX-2 expression.