Design, synthesis and biological evaluation of new 5-nitro benzimidazole derivatives as AT(1) antagonists with anti-hypertension activities

• Published in: Bioorganic & medicinal chemistry Vol. 22; no. 7; pp. 2294 - 2302
• Main Authors: Zhu, Weibo, Da, Yajing, Wu, Dan, Zheng, Huiling, Zhu, Linfeng, Wang, Li, Yan, Yijia, Chen, Zhilong
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier 01.04.2014
• Subjects: Biochemistry & Molecular Biology; Chemistry; Chemistry, Medicinal; Chemistry, Organic; Life Sciences & Biomedicine; Pharmacology & Pharmacy; Physical Sciences; Science & Technology; AT antagonist; Synthesis; Anti-hypertension; II RECEPTOR ANTAGONISTS; 5-Nitro benzimidazole derivatives
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2014.02.008

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.