Tanaka A, Ito K, Nishino S, Motoyama Y, Takasugi H
New Drug Research Laboratories, Fujisawa Pharmaceutical Co., Ltd., Osaka, Japan.
Chem Pharm Bull (Tokyo). 1994 Mar;42(3):560-9. doi: 10.1248/cpb.42.560.
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.
合成了一系列5-甲基-4-(3-吡啶基)-2-(取代苯并咪唑-5-基)咪唑衍生物，并对其抗血小板和血管舒张活性进行了测试。发现一些化合物具有强效活性和低急性毒性。特别是，5-甲基-4-(3-吡啶基)-2-(7-氯-6-甲氧基-2-甲基苯并咪唑-5-基)咪唑(26)和5-甲基-4-(3-吡啶基)-2-(7-氯-3-甲氧基-2-甲基苯并咪唑-5-基)咪唑(33)在大鼠体内10 mg/kg剂量下的体外抗血小板活性分别表现出63%或51%的抑制率，而它们即使分别在180或100 mg/kg剂量下也没有毒性。化合物33还表现出强效血管舒张活性(ED50 = 11微克/毫升)。对这些咪唑的酶学研究表明，新型咪唑抑制一些参与血小板聚集级联反应的酶，如环氧合酶、磷酸二酯酶(PDE)和血栓素A2合成酶。酶分析还表明，对PDE的抑制活性可能是这些咪唑具有血管舒张活性的原因。
