1-SUBSTITUTED 4-ARYL-5-PYRIDINYLIMIDAZOLES - A NEW CLASS OF CYTOKINE SUPPRESSIVE DRUGS WITH LOW 5-LIPOXYGENASE AND CYCLOOXYGENASE INHIBITORY POTENCY

A series of 1-alkyl- or -aryl-4-aryl-5-pyridinylimidazoles (A) were pr epared and tested for their ability to bind to a recently discovered p rotein kinase termed CSBP and to inhibit lipopolysaccharide (LPS)-stim ulated TNF production in mice. The kinase, CSBP, appears to be involve d in a signaling cascade initiated by a number of inflammatory stimuli and leading to the biosynthesis of the inflammatory cytokines IL-1 an d TNF. Two related imidazole classes (B and C) had previously been rep orted to bind to CSBP and to inhibit LPS-stimulated human monocyte IL- 1 and TNF production. The members of the earlier series exhibited vary ing degrees of potency as inhibitors of the enzymes of arachidonic aci d metabolism, PGHS-1 and 5-LO. Several of the more potent CSBP ligands and TNF biosynthesis inhibitors among the present series of N-1-alkyl ated imidazoles (A) were tested as inhibitors of PGHS-1 and 5-LO and w ere found to be weak to inactive as inhibitors of these enzymes. One o f the compounds, 9 (SE 210313) which lacked measureable activity as an inhibitor of the enzymes of arachidonate metabolism, and had good pot ency in the binding and in vivo TNF inhibition assays, was tested for antiarthritic activity in the AA rat model of arthritis. Compound 9 si gnificantly reduced edema and increased bone mineral density in this m odel.