Document Detail

Unique binding behavior of the recently approved angiotensin II receptor blocker azilsartan compared with that of candesartan.
MedLine Citation:
PMID:  23034464     Owner:  NLM     Status:  MEDLINE    
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.
Shin-ichiro Miura; Atsutoshi Okabe; Yoshino Matsuo; Sadashiva S Karnik; Keijiro Saku
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Publication Detail:
Type:  Comparative Study; Journal Article; Research Support, Non-U.S. Gov't     Date:  2012-10-04
Journal Detail:
Title:  Hypertension research : official journal of the Japanese Society of Hypertension     Volume:  36     ISSN:  1348-4214     ISO Abbreviation:  Hypertens. Res.     Publication Date:  2013 Feb 
Date Detail:
Created Date:  2013-02-05     Completed Date:  2013-07-23     Revised Date:  2014-03-13    
Medline Journal Info:
Nlm Unique ID:  9307690     Medline TA:  Hypertens Res     Country:  England    
Other Details:
Languages:  eng     Pagination:  134-9     Citation Subset:  IM    
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MeSH Terms
Angiotensin II Type 1 Receptor Blockers / metabolism*,  pharmacology
Benzimidazoles / metabolism*,  pharmacology
Blood Pressure / drug effects
COS Cells
Cercopithecus aethiops
Inositol Phosphates / metabolism
Oxadiazoles / metabolism*,  pharmacology
Protein Binding
Receptor, Angiotensin, Type 1 / drug effects,  metabolism*
Tetrazoles / metabolism*,  pharmacology
Grant Support
Reg. No./Substance:
0/Angiotensin II Type 1 Receptor Blockers; 0/Benzimidazoles; 0/Inositol Phosphates; 0/Oxadiazoles; 0/Receptor, Angiotensin, Type 1; 0/Tetrazoles; F9NUX55P23/azilsartan; S8Q36MD2XX/candesartan
Comment In:
Hypertens Res. 2013 Feb;36(2):107-8   [PMID:  23051655 ]
Erratum In:
Hypertens Res. 2013 May;36(5):476

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