Chemical Properties
White to Off-White Solid
Uses
Azilsartan is an analgesic and antiinflammatory drugs containing angiotensin II antagonists.
Uses
Azilsartan is an angiotensin II type 1 (AT1) receptor antagonist with IC50 of 2.6 nM
Definition
ChEBI: A benzimidazolecarboxylic acid that is benzimidazole-7-carboxylic acid substituted at position 2 by a methoxy group and at position 1 by a 2'-[(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl group. Used (as the prodrug, azilsartan medoxomil) f
r treatment of hypertension.
Clinical Use
Azilsartan is an orally active angiotensin II blocker which was approved and launched in Japan for
the treatment of arterial hypertension in May 2012. Azilsartan, which is marketed under the trade
name Azilva®, was discovered and developed by Takeda—the same firm which had developed and
launched a prodrug of azilsartan (azilsartan kamedoxomil, Edarbi®) in 2010. Azilsartan exhibits higher
potency and slower off-rate kinetics for type 1 angiotensin II receptors, which contributes to azilsartan’s
comparatively improved blood pressure lowering effect.
Synthesis
The most likely process-scale synthetic route likely mimics that which is disclosed in Takeda’s
patents, and this is described in the scheme below. Commercial available benzoic acid 21 was activated as
the correspndong acyl azide and underwent a Curtius rearrangement to give carbamate 22 in 57% yield
(three steps from compound 21). The resulting aniline 22 was then alkylated with commercial 4-
(bromomethyl)-2'-cyanobiphenyl 23 to give benzylamine 24 in 85% yield. Nitroamine 24 was then
exposed to mildly acidic conditions to affect Boc-removal prior to reduction via ferric chloride hydrate
in the presence of hydrazine hydrate. The resulting diamine 25 arose in 64% yield across the two-step
sequence. Interestingly, tt was found that metal catalysts under conventional hydrogenation conditions
caused partial debenzylation, which led the authors to arrive at the hydrazine/ferric chloride conditions.
Next, benzimidazole formation was achieved upon treatment of diamine 25 with ethyl orthocarbonate in
acetic acid. The resulting ethoxylbenzimidazole 26 was procured in 86% yield, and this benzonitrile was
further reacted with hydroxylamine hydrochloride and sodium methoxide to provide amidoxime 27 in
90% as white powder. Next, activation with ethyl chlorocarbonate gave 28 followed by heating in
refluxing xylene to give oxadiazolone 29 in 23% yield from hydroxyamidine 27. Finally ester 29 was
saponified with 2N LiOH in methanol to give azilsartan (V) in 84% yield.
An improved scalable route (Scheme below) to azilsartan was reported and features reproducibly better
yields.43 Hydroxyamidine 30 was treated with dimethyl carbonate and sodium methoxide, which
triggered they key cyclization along with concomitant transesterification to deliver 29. Milder aqueous
sodium hydroxide hydrolysis converted this methyl ester 29 to azilsartan (V) in 88-90% yield.
Enzyme inhibitor
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.
References
[1] YASUHISA KOHARA. Synthesis and Angiotensin II Receptor Antagonistic Activities of Benzimidazole Derivatives Bearing Acidic Heterocycles as Novel Tetrazole Bioisosteres 1[J]. Journal of Medicinal Chemistry, 1996, 39 26: 5228-5235. DOI:
10.1021/jm960547h[2] MAMI OJIMA. In vitro antagonistic properties of a new angiotensin type 1 receptor blocker, azilsartan, in receptor binding and function studies.[J]. Journal of Pharmacology and Experimental Therapeutics, 2011, 336 3: 801-808. DOI:
10.1124/jpet.110.176636[3] SOPHIE-DOROTHEE CLAS Rebecca N Rosa I Sanchez. Chemistry-enabled drug delivery (prodrugs): recent progress and challenges.[J]. Drug Discovery Today, 2014, 19 1: 79-87. DOI:
10.1016/j.drudis.2013.08.014
