Design, synthesis and evaluation of novel angiotensin II receptor 1 antagonists with antihypertensive activities

Abstract

A series of novel angiotensin II receptor 1 antagonists (1a-f, 2a-f) were designed, synthesized and evaluated. Radioligand binding assays showed that all these prepared compounds displayed nanomolar affinity for angiotensin II type 1 receptor, among which compound 1f was more affinitive than telmisartan at the same order of magnitude with an IC 50 value of 1.13 AE 1.68 nM. The antihypertensive effects showed that all these compounds could decrease blood pressure in a dose dependent manner on spontaneously hypertensive rats. And compound 2-(4- (1f), showed efficient and long-lasting effects in reducing blood pressure, with a maximal response lowered 55.98 AE 4.74 mmHg at 10 mg kg À1 and 35.82 AE 6.20 mmHg at 5 mg kg À1 , the antihypertensive effect of it lasted beyond 24 h which was better than telmisartan. In the single-dose pharmacokinetic experiments, compound 1f was absorbed efficiently and metabolized smoothly in Wistar rats. The values of C max , T max , AUC 0-72 , MRT 0-72 and T 1/2 were 17.92 AE 10.85 ng mL À1 , 2.60 AE 3.05 h, 252.85 AE 144.59 ng mL À1 h, 18.75 AE 0.43 h and 17.16 AE 4.24 h respectively. Compound 1f was distributed into tissues rapidly and extensively after oral administration and the level of it was the highest in the liver, followed by in the kidney, and the lowest in brain. The acute toxicity assays in ICR rats of 1f showed that it had low acute toxicity with an LD 50 value of 1459.89 mg kg À1 . These encouraging results make 1f an efficient, long-acting and safe antihypertensive drug candidate and deserving of further investigation.

Synthesis, Characterization and Biological Evaluation of Benzimidazole and Benzindazole Derivatives as Anti-hypertensive Agents

“…Before each systolic blood pressure measurement, the conscious rats were warmed with the cuff and the pulse wave transducer placed across the tail for 10 minutes.The mean arterial pressure (MABP) was calculated by the formula: MABP = (SBP − DBP)/3 + DBP. [6] 48 male Wistar rats were divided into eights groups, each comprising of 6 animals.…”

“…They show 10,000-30,000 times greater affinity for the AT1 receptor than for the AT2 receptor. [6]. The rennin angiotensin system (RAS) present in the kidney plays an important role in controlling the blood pressure.…”

“…Angiotensin II is an octapeptide produced in RAS from angiotensin I by angiotensin converting enzyme (ACE), and the component of the renninangiotensin system is responsible for one of the most powerful vasoconstrictors. Angiotensin II receptor blockers (ARBs) are the newest class of approved antihypertensive agents and have rapidly become established as one of the leading therapeutic drugs in Egyptian Journal of Chemistry http://ejchem.journals.ekb.eg/ the management of hypertension [6] .…”

“…Nowadays, many potent and safe ARBS are available in the market for the treatment of hypertension i.e., losartan, valsartan, irbesartan, candesartan, telmisartan etc [6]. Candesartan [7] and telmisartan are the two drugs have the benzimidazole ring and both are used in the treatment of the hypertension by blocking the AT1 receptors.…”

A Simple and Highly Selective Determination of Telmisartan at Sodium Dodecyl Sulfate Modified Pyrolytic Graphite Surface

“…Oral administration of TMS dose has been found to reduce the hypertension in several animal models . Hypertension increases the undesired symptoms and is associated with many complications like myocardial infarction, coronary heart disease and renal disease . The renin‐angiotensin system plays a substantial part in the growth and maintenance of hypertension.…”