In Vitro Antagonistic Properties of a New Angiotensin Type 1 Receptor Blocker, Azilsartan, in Receptor Binding and Function Studies

Abstract

The angiotensin II (AII) antagonistic action of azilsartan (AZL) [2-ethoxy-1-{[2Ј-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-1H-benzimidazole-7-carboxylic acid] was investigated in radioligand binding and function studies. AZL inhibited the specific binding of 125 I-Sar 1 -Ile 8 -AII to human angiotensin type 1 receptors with an IC 50 of 2.6 nM. The inhibitory effect of AZL persisted after washout of the free compound (IC 50 value of 7.4 nM). Olmesartan, telmisartan, valsartan, and irbesartan also inhibited the specific binding with IC 50 values of 6.7, 5.1, 44.9, and 15.8 nM, respectively. However, their inhibitory effects were markedly attenuated with washout (IC 50 values of 242.5, 191.6, Ͼ10,000, and Ͼ10,000 nM). AZL also inhibited the accumulation of AII-induced inositol 1-phosphate (IP1) in the cell-based assay with an IC 50 value of 9.2 nmol; this effect was resistant to washout (IC 50 value of 81.3 nM). Olmesartan and valsartan inhibited IP1 accumulation with IC 50 values of 12.2 and 59.8 nM, respectively. The activities of these compounds were markedly reduced after washout (IC 50 value of 908.5 and 22,664.4 nM). AZL was defined as an inverse agonist in an experiment by using a constitutively active mutant of human angiotensin type 1 receptors. In isolated rabbit aortic strips, AZL reduced the maximal contractile response to AII with a pDЈ 2 value of 9.9. The inhibitory effects of AZL on contractile responses induced by AII persisted after the strips were washed; these inhibitory effects were more potent than those of olmesartan. These results suggest that AZL is a highly potent and slowly dissociating AII receptor blocker. Its tight receptor binding might be expected to produce potent and long-lasting antihypertensive effects in preclinical and clinical settings.

Comparative study to evaluate efficacy and safety of azilsartan and telmisartan in patients with grade I-II essential hypertension

“…[29][30][31] During gastrointestinal absorption, azilsartan medoxidil is rapidly hydrolyzed to azilsartan, the bioactive molecule that selectively and competitively blocks angiotensin induced activation of AT1 receptor in an insurmountable fashion. 32,33 Azilsartan in clinically approved doses as azilsartan medoxomil has been shown to lower 24-hour BP in hypertensive patients significantly more than the maximum approved dose of olmesartan medoxomil, the later being considered by some to be one of the most potent ARBs for lowering BP. [34][35][36] Given the close structural relationship between azilsartan and candesartan, head to head studies comparing the BP effects of these two drugs are of particular interest.…”

Comparative study of efficacy and adverse effects profile of azilsartan, olmesartan and candesartan in the control of essential hypertension

“…[23][24][25] During gastrointestinal absorption , azilsartan medoxidil is rapidly hydrolyzed to azilsartan, the bioactive molecule that selectively and competitively blocks angiotensin induced activation of AT1 receptor in an insurmountable fashion. 26,27 Azilsartan in clinically approved doses as azilsartan medoxomil has been shown to lower 24-hour BP in hypertensive patients significantly more than the maximum approved dose of olmesartan medoxomil, the later being considered by some to be one of the most potent ARBs for lowering BP. [28][29][30] Given the close structural relationship between azilsartan and candesartan, head to head studies comparing the BP effects of these two drugs are of particular interest.…”

Hypertension Therapeutics Update: A Brief Clinical Summary on Azilsartan, Cilnidipine and Nebivolol

“…Azilsartan in the dose range of 40 to 80 mg/day produces significant reduction in the blood pressure levels and thus may reduce the chronic disease burden. 8,9 The optimal dose of azilsartan is 80 mg/day although a lower dosage (40 mg) can be utilized for patients on diuretics and other antihypertensive drugs. Angiotensin receptor blockers have a useful role in the management of hypertension and its complications.…”