Synthesis and biological evaluation of novel potent angiotensin II receptor antagonists with anti-hypertension effect

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• 作者：Yong-yan Nie ; Ya-jing Da ; Hao Zheng ; Xiao-xia Yang ; Lin Jia ; Cai-hong Wen ; Li-sha Liang ; Juan Tian ; Zhi-long Chen ; ^{zlchen1967@yahoo.com}
• 关键词：Angiotensin II receptor antagonists ; Hypertension ; Synthesis ; Acute toxicity
• 刊名：Bioorganic and Medicinal Chemistry
• 出版年：2012
• 期刊代码：9_09680896
• 类别：ch
• 出版时间：15 April, 2012
• 卷：20
• 期：8
• 页码：2747-2761
• 文件大小：771 K

摘要

A series of novel angiotensin II type 1 receptor antagonists were prepared. Radioligand binding assay suggested that compounds 1b and 1c could be recognized by the AT₁ receptor with an IC₅₀ value of 1.6 卤 0.09 nM and 2.64 卤 0.7 nM, respectively. In vivo anti-hypertension experiments showed that compounds (1a, 1b, 1c, 1e) elicited a significant decrease in SBP and DBP of spontaneous hypertensive rats (SHRs). The antihypertensive effects maintained for 10 h, which indicated that these compounds had a favorable blood pressure-lowering effect. Acute toxicity testing suggested that the LD₅₀ value of compound 1b was 2316.8 mg/kg which was lower than valsartan (LD₅₀ = 307.50 mg/kg) but higher than losartan (LD₅₀ = 2248 mg/kg). So they could be considered as novel anti-hypertension candidates and deserved for further investigation.