Unique binding behavior of the recently approved angiotensin II receptor blocker azilsartan compared with that of candesartan

Abstract

The angiotensin II type 1 (AT 1) receptor blocker (ARB) candesartan strongly reduces blood pressure (BP) in patients with hypertension and has been shown to have cardioprotective effects. A new ARB, azilsartan, was recently approved and has been shown to provide a more potent 24-h sustained antihypertensive effect than candesartan. However, the molecular interactions of azilsartan with the AT 1 receptor that could explain its strong BP-lowering activity are not yet clear. To address this issue, we examined the binding affinities of ARBs for the AT 1 receptor and their inverse agonist activity toward the production of inositol phosphate (IP), and we constructed docking models for the interactions between ARBs and the receptor. Azilsartan, unlike candesartan, has a unique moiety, a 5-oxo-1,2,4-oxadiazole, in place of a tetrazole ring. Although the results regarding the binding affinities of azilsartan and candesartan demonstrated that these ARBs interact with the same sites in the AT 1 receptor (Tyr 113, Lys 199 and Gln 257), the hydrogen bonding between the oxadiazole of azilsartan-Gln 257 is stronger than that between the tetrazole of candesartan-Gln 257, according to molecular docking models. An examination of the inhibition of IP production by ARBs using constitutively active mutant receptors indicated that inverse agonist activity required azilsartan-Gln 257 interaction and that azilsartan had a stronger interaction with Gln 257 than candesartan. Thus, we speculate that azilsartan has a unique binding behavior to the AT 1 receptor due to its 5-oxo-1,2,4-oxadiazole moiety and induces stronger inverse agonism. This property of azilsartan may underlie its previously demonstrated superior BP-lowering efficacy compared with candesartan and other ARBs. © 2013 The Japanese Society of Hypertension All rights reserved.