Pharmacological profile of ZD1611, a novel, orally active endothelin ET_A receptor antagonist

作     者：Wilson, C Hunt, SJ Tang, E Wright, N Kelly, E Palmer, S Heys, C Mellor, S James, R Bialecki, R 

作者机构：Zeneca Pharmaceut Macclesfield SK10 4TG Cheshire England 

出 版 物：《JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS》 (药理学与实验治疗学杂志)

年 卷 期：1999年第290卷第3期

页      面：1085-1091页

核心收录：

学科分类：1007[医学-药学(可授医学、理学学位)] 1006[医学-中西医结合] 100706[医学-药理学] 100602[医学-中西医结合临床] 10[医学] 

主　　题：投药 口服 主动脉/药物作用 主动脉/生理学 结合 竞争性 剂量效应关系 药物 内皮缩血管肽1/代谢 内皮缩血管肽1/药理学 内皮缩血管肽类/药理学 碘放射性同位素 动力学 肽碎片/药理学 吡嗪类/代谢 吡嗪类/药理学 放射配体测定 大鼠 Sprague-Dawley 受体 内皮素A 受体 内皮素B 受体 内皮缩血管肽/拮抗剂和抑制剂 磺胺类/代谢 磺胺类/药理学 动物 狗 女(雌)性 人类 男(雄)性 小鼠 大鼠 

摘      要：The endothelins (ETs), potent vasoconstrictor peptides, have been implicated in the pathogenesis of various cardiovascular disorders. In the present study, we describe the novel, potent, orally active, selective ETA receptor antagonist ZD1611 [3-(4-[3-(3- methoxy-5-methylpyrazin-2-ylsulfamoyl)-2-pyridyl]phenyl)-2,2-dimethylpropanoic acid]. ZD1611 competitively inhibited I-125-labeled ET-1 binding at human cloned ETA and ETB receptors with pIC(50) values of 8.6 +/- 0.1 and 5.6 +/- 0.1, respectively, showing 1000-fold selectivity for the ETA receptor. ZD1611 caused a parallel rightward shift of the concentration response curve to ET-1 in the rat isolated aorta yielding a concentration of antagonist that caused a 2-fold rightward shift in the ET-1-response curve (pA(2)) of 7.5 +/- 0.3. When administered i.v. to anesthetized rats and dogs, ZD1611 caused dose-related rightward shifts of partial dose-response curves to the precursor of ET-1, big ET-1. Threshold doses for significant antagonist activity were determined as 0.1 mg/kg and 0.3 mg/kg in the rat and dog, respectively. Importantly, ZD1611 was able to reverse an established big ET-l-induced presser response in pithed rats in the presence of continuous big ET-1 infusion. Failure of ZD1611 to inhibit the BQ3020 (ETB selective)-induced depressor response in pithed rats indicated alack of activity at the endothelial ET, receptor. ZD1611 was orally active in the rat at 0.3 mg/kg and had a duration of action of more than 7 h, and, in the dog, a dose of 0.6 mg/kg p.o. was active for at least 6 h. In conclusion, these data demonstrate that ZD1611 is a potent and orally active, selective ETA receptor antagonist with a long duration of action which may be of therapeutic use.