Other Compounds

The cannabinoid receptor agonist, R-( + )-WIN-55,212-2 (12), has shown efficacy in controlling disease progression in animal models of multiple sclerosis (MS). This effect has been attributed to its ability to reduce migration of leukocytes into the central nervous system [90], in which adhesion molecules are believed to be involved. Compound 12, but not its enantiomer, S-(-)-WIN-55,212-2, strongly inhibited IL-1-induced expression of VCAM-1 on astrocytoma and A-172 glioblastoma cells. Interestingly, S-(-)-WIN-55,212-2 showed no efficacy in models of MS. The inhibitory effect of 12 on VCAM-1 expression is not believed to be mediated via cannabinoid receptors, since both selective cannabinoid receptor antagonists and pertussis toxin failed to affect it. Experimental data suggest that 12 blocks IL-1 signaling by inhibiting the transactivation potential of nuclear factor-kB (NF-kB) [91].

In recent years, dual 5-lipooxygenase (5-LOX) and cyclooxygenase (COX) inhibitors, interfering with both prostaglandin and leukotriene pathways in the arachidonic acid cascade, have emerged as possible alternatives to non-steroidal anti-inflammatory drugs (NSAIDs) which interact with the prostaglandin pathway only. The hope for dual 5-LOX/COX inhibition is to alleviate the side effects related to sole COX-inhibition, especially those exerted by selective COX-2 inhibitors. Licofelone (13), a dual 5-LOX/COX inhibitor, attenuated VCAM-1 expression in inflammatory endothelial cells in vitro. In a flow chamber assay, it dose-dependently decreased both the rolling and adhesion of leukocytes on endothelial cells. In contrast, no effects were found with the non-selective COX inhibitor indomethacin, the potent and selective 5-LOX inhibitor ZD-2138, or the selective COX-2 inhibitor celecoxib, or the combination of ZD-2138 with celecoxib. In a mouse peritonitis model, licofelone markedly reduced leukocyte accumulation [92].

COOH

COOH

KR-31378 (14) [93] inhibited VCAM-1 expression and decreased adhesion and migration of monocytes in a dose-dependent manner. It has shown a neuropro-tective effect for ischemia-reperfusion damage in rat brain. In LDL receptor-knockout mice which were fed a high-fat, high-cholesterol diet, treatment with 14 significantly inhibited fatty streak formation and macrophage accumulation on the artery wall, indicating its potential for treating atherosclerosis. Experimental data also showed that 14 might work by decreasing NF-kB activation [94].

3

Methimazole (15) is a tautomeric cyclic thione used clinically for various autoimmune diseases. Several observations suggest that 15 could be an antiinflammatory agent through inhibition of adhesion molecules [95]. For example, it reduced sVCAM-1 levels in the circulation of patients with Graves' disease [96]. A phenyl derivative (structure undisclosed) of methimazole [97] was far more effective in experimental models of lupus and diabetes than methimazole [98]. The phenyl analog inhibited TNF-a-induced VCAM-1 mRNA and protein expression in human airway epithelial cells (HAECs), reduced TNF-a-induced monocytic (U937) cell adhesion to HAECs under in vitro flow conditions, inhibited TNF-a-induced interferon regulatory factor-1 (IRF-1) binding to VCAM-1 promoter, and reduced TNF-a-induced IRF-1 expression in HAECs [95].

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