title: Studies on anti-platelet agents. II. Synthesis and platelet-inhibitory activity of 5-methyl-4-(3-pyridyl)-2-(substituted benzimidazol-5-yl)imidazoles.
abstract: 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 (ED50 = 11 micrograms/ml). Enzyme studies on these imidazoles showed that the novel imidazoles inhibit some enzymes which are involved in the platelet aggregation cascade such as cyclooxygenase, phosphodiesterase (PDE), and thromboxane A2 synthetase. The enzyme assay also suggested that the inhibitory activity on PDE may account for the vasodilatory activity of these imidazoles.
authors.affiliation: New Drug Research Laboratories, Fujisawa Pharmaceutical Co., Ltd., Osaka, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Tanaka
authors.forename: K
authors.initials: K
authors.lastname: Ito
authors.forename: S
authors.initials: S
authors.lastname: Nishino
authors.forename: Y
authors.initials: Y
authors.lastname: Motoyama
authors.forename: H
authors.initials: H
authors.lastname: Takasugi
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D012756:Sheep; D013329:Structure-Activity Relationship; D014665:Vasodilator Agents / Q000138:chemical synthesis / Q000494:pharmacology
chemical_list: D007093:Imidazoles; D010975:Platelet Aggregation Inhibitors; D014665:Vasodilator Agents