Zhu Weibo, Bao Xiaolu, Ren He, Da Yajing, Wu Dan, Li Fuming, Yan Yijia, Wang Li, Chen Zhilong
Department of Pharmaceutical Science and Technology, College of Chemistry and Biology, Donghua University, Shanghai 201600, China.
State Key Laboratory for Modification of Chemical Fibers and Polymer Materials, College of Materials Science and Engineering, Donghua University, Shanghai 201620, China.
Eur J Med Chem. 2016 Jun 10;115:161-78. doi: 10.1016/j.ejmech.2016.03.021. Epub 2016 Mar 12.
The design, synthesis, in vitro and in vivo evaluation of 6-substituted benzimidazole with 1, 4-disubsituted or 1, 5-disubsituted indole derivatives as novel angiotensin II receptor antagonists are outlined. Radioligand binding assays showed that several 6-substituted benzimidazole derivatives displayed high affinities binding to the angiotensin II type 1 receptor at the same order of magnitude to telmisartan. The biological evaluation on spontaneously hypertensive rats showed that 2-[4-[[2-n-propyl-4-methyl-6-(1-methylbenzimidazol-2-yl)benzimidazole-1-yl]methyl]-1H-indol-1-yl]benzoic acid, 1c, could cause significant decrease on MBP in a dose dependent manner. Its maximal response lowered 53 mmHg of MBP at 5 mg/kg and 64 mmHg of MBP at 10 mg/kg after oral administration, and the significant antihypertensive effect lasted beyond 24 h, which was better than both losartan and telmisartan. A study designed to determine acute toxicity showed that 1c had low acute toxicity with no significant changes in the weight and no obvious untoward reactions. The encouraging results make 1c an effective and durable anti-hypertension drug candidate and deserve further investigation for therapeutic application.
本文概述了以1,4-二取代或1,5-二取代吲哚衍生物为新型血管紧张素II受体拮抗剂的6-取代苯并咪唑的设计、合成、体外和体内评价。放射性配体结合试验表明，几种6-取代苯并咪唑衍生物对血管紧张素II 1型受体具有高亲和力，其亲和力与替米沙坦处于同一数量级。对自发性高血压大鼠的生物学评价表明，2-[4-[[2-正丙基-4-甲基-6-(1-甲基苯并咪唑-2-基)苯并咪唑-1-基]甲基]-1H-吲哚-1-基]苯甲酸（1c）可使平均动脉压（MBP）呈剂量依赖性显著降低。口服给药后，其最大效应在5mg/kg时使MBP降低53mmHg，在10mg/kg时使MBP降低64mmHg，且显著的降压作用持续超过24小时，优于氯沙坦和替米沙坦。一项旨在确定急性毒性的研究表明，1c的急性毒性较低，体重无显著变化，也无明显不良反应。这些令人鼓舞的结果使1c成为一种有效且持久的抗高血压药物候选物，值得进一步研究其治疗应用。
