Trova M P, Wissner A, Carroll M L, Kerwar S S, Pickett W C, Schaub R E, Torley L W, Kohler C A
Oncology and Immunology Section, American Cyanamid Company, Lederle Laboratories, Pearl River, New York 10965.
J Med Chem. 1993 Mar 5;36(5):580-90. doi: 10.1021/jm00057a008.
A series of platelet activating factor (PAF) antagonists containing a quaternary pyridinium ring connected through an amide, imide, or carbamate linkage to a substituted aromatic ring was prepared. Of these compounds, those containing a branched imide linkage of the form (CON-(COCH3)CH2, 37-51, and 59) generally showed excellent PAF antagonist properties in vitro. Structure-activity relationships within this series of compounds were studied extensively with respect to substituents and the position of substitution in both the aromatic and pyridinium rings. Several of these compounds (40 and 44) showed in vitro PAF antagonism at less than 0.1 microM and are as potent as CV-6209, the most potent PAF antagonist reported in the literature. Less active PAF antagonists were those bearing simple amide linkages (20-23, 27-29, and 31-35), linear imide linkages (62-63), or carbamate linkages (66 and 68), between the two aromatic rings. A number of our PAF antagonists were tested in vivo in mice and rabbits for their ability to protect these animals against a lethal injection of PAF. Those antagonists that are particularly potent (IC50 < 0.1 microM) provide excellent protection against an LD97 dose of PAF in rabbits. The relationships between structure and activity in vitro and in vivo are presented and compared to literature standards.
制备了一系列血小板活化因子（PAF）拮抗剂，这些拮抗剂含有通过酰胺、酰亚胺或氨基甲酸酯键连接到取代芳环上的季铵吡啶环。在这些化合物中，那些含有（CON-(COCH3)CH2、37 - 51和59）形式的支链酰亚胺键的化合物通常在体外表现出优异的PAF拮抗特性。针对芳环和吡啶环上的取代基及取代位置，对该系列化合物的构效关系进行了广泛研究。其中几种化合物（40和44）在体外小于0.1微摩尔时表现出PAF拮抗作用，其效力与文献中报道的最有效的PAF拮抗剂CV - 6209相当。活性较低的PAF拮抗剂是那些在两个芳环之间带有简单酰胺键（20 - 23、27 - 29和31 - 35）、线性酰亚胺键（62 - 63）或氨基甲酸酯键（66和68）的化合物。我们的许多PAF拮抗剂在小鼠和兔子体内进行了测试，以考察它们保护这些动物免受致死剂量PAF注射的能力。那些特别有效的拮抗剂（IC50 < 0.1微摩尔）能为兔子提供针对LD97剂量PAF的出色保护。本文展示了体外和体内的构效关系，并与文献标准进行了比较。
