Dual inhibitors of thromboxane A2 synthase and 5-lipoxygenase with scavenging activity of active oxygen species (AOS). Synthesis of a novel series of (3-pyridylmethyl)benzoquinone derivatives
作者:Shigenori Ohkawa、Shinji Terao、Zenichi Terashita、Yumiko Shibouta、Kohei Nishikawa
DOI:10.1021/jm00105a042
日期:1991.1
A novel series of (3-pyridylmethyl)benzoquinone derivatives was molecular designed and synthesized for the dual purpose of inhibiting thromboxane A2 and leukotriene biosynthesis enzymes and scavenging active oxygen species (AOS). They were evaluated for inhibition of TXA2 synthase, inhibition of 5-lipoxygenase, and for their scavenging activity of AOS using the thiobarbituric acid method. 2,3,5-Tr
为了抑制血栓烷A2和白三烯生物合成酶并清除活性氧(AOS)的双重目的,设计并合成了一系列新型的(3-吡啶基甲基)苯醌衍生物。使用硫代巴比妥酸法评价了它们对TXA2合酶的抑制,对5-脂氧合酶的抑制以及对AOS的清除活性。2,3,5-三甲基-6-(3-吡啶基甲基)-1,4-苯醌(24,CV-6504)是最有前途的衍生物,因为它显示出有效的AOS清除活性(抑制大鼠脑匀浆中的脂质过氧化作用: IC50 = 1.8 x 10(-6)M)以及对这两种酶的有效,特异性和良好平衡的抑制作用(对人血中TXA2合酶的抑制作用,IC50 = 3.3 x 10(-7)M;抑制作用对人血中的5-脂氧合酶的抑制作用,IC50 = 3.6 x 10(-7)M)。在大鼠模型中由阿霉素诱导的蛋白尿中,每天10 mg / kg(po)的化合物24抑制蛋白尿的作用超过50%。但是,不能通过单用血栓烷A2合酶[(E)-7-苯基-