Design, synthesis and biological evaluation of new 5-nitro benzimidazole derivatives as AT1 antagonists with anti-hypertension activities

被引:48
作者
Zhu, Weibo [1 ]
Da, Yajing [1 ]
Wu, Dan [1 ]
Zheng, Huiling [1 ]
Zhu, Linfeng [1 ]
Wang, Li [1 ]
Yan, Yijia [1 ]
Chen, Zhilong [1 ]
机构
[1] Donghua Univ, Dept Pharmaceut Sci & Technol, Coll Chem & Biol, Shanghai 201620, Peoples R China
关键词
5-Nitro benzimidazole derivatives; AT(1) antagonist; Synthesis; Anti-hypertension; II RECEPTOR ANTAGONISTS;
D O I
10.1016/j.bmc.2014.02.008
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The design, synthesis, in vitro and in vivo evaluation of 5-nitro benzimidazole with 1,4-disubsituted or 1,5-disubsituted indole derivatives as novel angiotensin II receptor antagonist is outlined. Radioligand binding assays showed that 2-(4-((2-butyl-5-nitro-1H-benzo[d] imidazol-1-yl) methyl)-1H-indol-1-yl) benzoic acid, compound 3, displayed a high affinity for the angiotensin II type 1 receptor with IC50 value of 1.03 +/- 0.26 nM. The biological evaluation on spontaneously hypertensive rats and renal hypertensive rats showed that 3 could cause significant decrease on MBP in a dose dependent manner, whose maximal response lowered 30 mmHg of MBP at 5 mg/kg and 41 mmHg of MBP at 10 mg/kg after oral administration, and the significant antihypertensive effect lasted beyond 24 h, which is better than Losartan. Taken together 3 could be considered as an effective and durable anti-hypertension drug candidate. These encouraging results are deserved of further investigation towards its use for therapeutic benefit. (c) 2014 Elsevier Ltd. All rights reserved.
引用
收藏
页码:2294 / 2302
页数:9
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