Studies on Anti-platelet Agents. II. Synthesis and Platelet-Inhibitory Activity of 5-Methyl-4-(3-pyridyl)-2-(substituted Benzimidazol-5-yl)imidazoles

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A series of 5-methyl-4-(3-pyridyl)-2-(substituted benzimidazol-5-yl)imidazole derivatives was synthesized and tested for anti-platelet and vasodilatory activities. Some compounds were found to have potent activities and low acute toxicity. In particular, 5-methyl-4-(3-pyridyl)-2-(7-chloro-6-methoxy-2-methylbenzimidazol-5-yl)imidazole (26) and 5-methyl-4-(3-pyridyl)-2-(7-chloro-3-methoxy-2-methylbenzimidazol-5-yl)imidazole (33) exhibited 63% or 51% inhibition at a dose of 10 mg/kg for anti-patelet activity ex vivo in rats, respectively, while they showed no toxicity even at 180 or 100 mg/kg, respectively. Compound 33 also exhibited potent vasodilatory activity (ED_<50>=11 μg/ml). Enzyme studies on these imidazoles showed that the novel imidazoles inhibit some snzymes which are involved in the platelet aggregation cascade such as cyclooxygenase, phosphodiesterase (PDE), and thromboxane A_2 synthetase. The enzyme assay also suggested that the inhibitory activity on PDE may account for the vasodilatory activity of these imidazoles.
社団法人日本薬学会の論文
1994-03-15