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説明

Azilsartan medoxomil (Edarbi), an angiotensin II receptor antagonist, was approved by the U.S. FDA in February 2011 for the treatment of hypertension in adults. The discovery of azilsartan was the result of a medicinal chemistry effort to identify an ARB with a different carboxylic acid isostere than the ones found in the marketed ARBs. Several of the marketed ARBs use a tetrazole group as a carboxylic acid isostere. The medicinal chemistry approach that led to azilsartan involved the replacement of this commonly used tetrazole with a 5-oxo-1,2,4-oxadiazole group. Azilsartan can be synthesized by Suzuki coupling of p-tolyl boronic acid to 2-bromobenzonitrile, followed by bromination of the methyl group. The bromide is displaced to introduce a protected 2-ethoxy-1H-benzo[d] imidazole-7-carboxylate. The cyano group is converted to a hydroxylamidine, followed by reaction with an alkyl-chloroformate and intramolecular cyclization to form the 5-oxo-1,2,4-oxadiazole ring. The acid is then deprotected and converted to a prodrug. The parent, azilsartan has been extensively characterized in vitro and compared with other marketed AT1 antagonists olmesartan, valsartan, telmisartan, irbesartan, and candesartan. Azilsartan was found to be a potent (IC₅₀=2.6 nM), selective, inverse agonist of the AT₁ receptor. From washout experiments, azilsartan was found have slow dissociation from the receptor and thus is characterized as an insurmountable antagonist.