863031-21-4

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.

Takeda (United States)

Azilsartan medoxomil is a long-acting angiotensin II receptor blocker (ARB) that is used to lower hypertension. When Azilsartan medoxomil enters the gastrointestinal tract, it is rapidly converted to its active form, Azilsartan (A926900).

ChEBI: A carboxylic ester obtained by formal condensation of the carboxy group of azilsartan with the hydroxy group of 4-(hydroxymethyl)-5-methyl-1,3-dioxol-2-one. A prodrug for azilsartan, it is used for treatment of hypertension.

Edarbi

This angiotensin II receptor antagonist and its membrane-permeant pro- drug (FWdrug = 456.45 g/mol; CAS 147403-03-0; FWpro-drug = 568.53 g/mol; CAS 863031-21-4), also named TAK-536 (drug) and TAK-491 (pro-drug), Edarbi?, and (5-methyl-2-oxo-1,3-dioxol-4-yl) methyl 2-ethoxy-1- ([2'- (5- oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-4-yl]methyl) -1H-benzimid- azole-7-carboxylate, lowers blood pressure by blocking the binding of the vasopressor hormone, angiotensin II, to the angiotensin Type-1 receptor (or AT1-receptor), IC50 = 45 nM. Blocking of AT1 receptors reduces blood pressure by promoting vasodilation, decreasing vasopressin secretion, and reducing aldosterone production/secretion. The pro-drug is hydrolyzed to the active moiety in the gastrointestinal (GI) tract during the absorption phase. The estimated absolute bioavailability of azilsartan is 60%. Absorption is unaffected by food, and peak plasma concentrations are reached within several hours before its eventual deactivation by cytochrome P450 (CYP2C9), biological t1/2 ≈ 11 hours. The U.S. FDA approved Edarbi for the treatment of high blood pressure in adults in February, 2011.

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