Uno T, Ozeki Y, Koga Y, Chu G N, Okada M, Tamura K, Igawa T, Unemi F, Kido M, Nishi T
Third Institute of New Drug Research, Otsuka Pharmaceutical Co., Ltd., Tokushima, Japan.
Chem Pharm Bull (Tokyo). 1995 Oct;43(10):1724-33. doi: 10.1248/cpb.43.1724.
A search for potent inhibitors of release of 12(S)-hydroxyeicosatetraenoic acid (12-HETE), which plays an important role in the pathogenesis of various circulatory disorders and arteriosclerosis, led us to 6-[4-(1-cyclohexyl-5-tetrazolyl)butoxy]-3,4-dihydro-2(1H)-quinolinone (cilostazol) and 2(1H)-quinolinone derivatives having an azole group in the side chain. Many 2(1H)-quinolinone derivatives were synthesized and tested in vitro for the inhibitory activity in human platelets. 3,4-Dihydro-6-[3-(1-o-tolylimidazol-2-yl)sulfinylpropoxy]-2( 1H)-quinolinone (5k) was found to be one of the most potent inhibitors of 12-HETE release, being more potent than esculetin. In addition, the sulfoxide 5k showed in vivo inhibitory activity on platelet adhesion in rats. Since 5k is racemic, the enantiomers were prepared and their potencies were compared in vitro and in vivo. (S)-(+)-5k had the best pharmacological profile and was selected as a candidate drug for further development. The structure-activity relationships are discussed.
对12(S)-羟基二十碳四烯酸（12-HETE）释放的强效抑制剂进行研究，12-HETE在各种循环系统疾病和动脉硬化的发病机制中起重要作用，这使我们发现了6-[4-(1-环己基-5-四唑基)丁氧基]-3,4-二氢-2(1H)-喹啉酮（西洛他唑）以及侧链带有唑基的2(1H)-喹啉酮衍生物。合成了许多2(1H)-喹啉酮衍生物，并在体外测试其对人血小板的抑制活性。发现3,4-二氢-6-[3-(1-邻甲苯基咪唑-2-基)亚磺酰基丙氧基]-2(1H)-喹啉酮（5k）是12-HETE释放的最有效抑制剂之一，比七叶亭更有效。此外，亚砜5k在体内对大鼠血小板黏附具有抑制活性。由于5k是外消旋体，制备了其对映体并在体外和体内比较了它们的效力。(S)-(+)-5k具有最佳的药理学特征，被选为进一步开发的候选药物。讨论了构效关系。
