N-Phenyl indole derivatives as AT1 antagonists with anti-hypertension activities: Design, synthesis and biological evaluation.

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.

Synthesis and pharmacological evaluation of a novel AT1 angiotensin II receptor antagonist with anti-hypertension and anti-tumor effects.

A new compound 2-(4-((2-butyl-5-nitro-1H-benzo[d]imidazol-1-yl)methyl)-1H-indol-1-yl) benzamide (1) was designed, synthesized and evaluated as a novel AT1 receptor antagonist. Compound 1 displayed high affinity to AT1 receptor with an IC50 value of 1.65 ± 0.2 nM in radio-ligand binding assays. It had an efficient and long-lasting effect in reducing blood pressure which could last for more than 12 h at the dose of 10 mg/kg in spontaneously hypertensive rats. Acute toxicity tests suggested that compound 1 was safe with the LD50 value of 2519.81 mg/kg. Besides, in vitro and in vivo tests suggested its anti-proliferative and anti-tumor activities, respectively. So compound 1 could be considered as a novel anti-hypertension, anti-tumor candidate and deserved further investigation.

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

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±0.26nM. 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 30mmHg of MBP at 5mg/kg and 41mmHg of MBP at 10mg/kg after oral administration, and the significant antihypertensive effect lasted beyond 24h, 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.

Synthesis and biological evaluation of new fluorine substituted derivatives as angiotensin II receptor antagonists with anti-hypertension and anti-tumor effects.

The synthesis and pharmaceutical activity of new potent non-tetrazole angiotensin II (Ang II) receptor antagonists were described. These compounds were fluorine substituted derivatives of Losartan, Valsartan and Irbesartan with carboxylic acid group as replacements to the known potent tetrazole moiety at the 2'-biphenyl position. Their activities were evaluated by Ang II receptor binding assay as well as by in vivo assay. All of the synthesized compounds showed nanomolar affinity for the AT(1) receptor subtype. The vivo biological evaluation showed that compounds 1a, 2 and 4 produced a dose-dependent antihypertensive effect both in spontaneously hypertensive rats (SHR) and renal hypertensive rats (RHR). Compound 4 especially showed an efficient and long-lasting effect in reducing blood pressure which can last more than 24 h at dose of 10 mg/kg in SHR, which was much better than control Losartan and Valsartan. Compound 4 can also inhibit the prostate cancer in vitro and in vivo. So compound 4 was selected for in-depth investigation as potent, novel and long-lasting non-tetrazole anti-hypertension and anti-tumor drug candidate.

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

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 AT(1) receptor with an IC(50) value of 1.6 ± 0.09 nM and 2.64 ± 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 LD(50) value of compound 1b was 2316.8 mg/kg which was lower than valsartan (LD(50)=307.50 mg/kg) but higher than losartan (LD(50)=2248 mg/kg). So they could be considered as novel anti-hypertension candidates and deserved for further investigation.