145303-52-2Relevant articles and documents
N-Phenyl indole derivatives as AT1 antagonists with anti-hypertension activities: Design, synthesis and biological evaluation
Zhu, Weibo,Bao, Xiaolu,Ren, He,Da, Yajing,Wu, Dan,Li, Fuming,Yan, Yijia,Wang, Li,Chen, Zhilong
, p. 161 - 178 (2016/04/05)
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.
Design, synthesis and biological evaluation of new 5-nitro benzimidazole derivatives as AT1 antagonists with anti-hypertension activities
Zhu, Weibo,Da, Yajing,Wu, Dan,Zheng, Huiling,Zhu, Linfeng,Wang, Li,Yan, Yijia,Chen, Zhilong
, p. 2294 - 2302 (2014/04/17)
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-n
Non-peptide angiotensin II receptor antagonists. 1. Design, synthesis, and biological activity of N-substituted indoles and dihydroindoles
Dhanoa,Bagley,Chang,Lotti,Chen,Kivlighn,Zingaro,Siegl,Patchett,Greenlee
, p. 4230 - 4238 (2007/10/02)
A series of N-acylated indoles (12-18), N-alkylated indoles (19-24), N- acylated dihydroindoles (26-30), and N-alkylated dihydroindoles (31-34) were synthesized and evaluated in the in vitro AT1 (rabbit aorta) and AT2 (rat midbrain) binding assay. The carboxylic acid 3-[[N-(2-carboxy-3,6- dichlorobenzoyl)-5-indolyl]methyl]-5,7-dimethyl-2-ethyl-3H-imidazo[4,5- b)pyridine (14b) was found to be the most potent AT1 (IC50 = 0.8 nM) antagonist in the N-acylated indole series and displayed a 25-fold higher potency than the parent unsubstituted derivative 14a (AT1 IC50 = 20 nM) and a 22-fold greater potency than the corresponding dihydroindole analog 27 (AT1 IC50 = 18 nM). Replacement of the terminal carboxyl (COOH) of 14a with the bioisostere tetrazole in 16 (AT1 IC50 = 5 nM, AT2 IC50 = 130 nM) not only improved the AT1 potency by 4-fold but also resulted in a 50- fold increase in AT2 activity. In the N-alkylated indole series, the tetrazole 3-[[N-(2-tetrazol-5-yl-6-chlorobenzyl)-5-indolyl]methyl]-5,7- dimethyl-2-ethyl-3H-imidazo[4,5,-b]pyridine (24) exhibited the highest AT1 (IC50 = 1 nM) activity, revealing a 230-fold increase in AT1 activity as a result of the incorporation of the isosteric tetrazole for the carboxyl (COOH) of 20 and a nearly 9-fold increase over the corresponding deschloro analog 22 (AT1 IC50 = 8.7 nM). Tetrazole 34 was identified as the most potent (AT1 IC50 = 18 nM) AT1 receptor antagonist in a structurally distinct series of compounds derived from N-alkylation of dihydroindole 25. A new class of highly potent (14b, AT1 IC50 = 0.8 nM; 24, AT1 IC50 = 1 nM) AT1-selective non-peptide AII receptor antagonists derived from N- substituted indoles and dihydroindoles is disclosed. Tetrazole 24 of the N- alkylated indole series displayed good in vivo activity by blocking the AII- induced pressor response for 5.5 h after intravenous administration in conscious normotensive rats at a 1.0 mg/kg dose level.
