Azilsartan

Description

Azilsartan is an effective medication that serves as an antagonist of the angiotensin II type 1 receptor, known as AT1. It is the active metabolite of the prodrug azilsartan medoxomil, which is converted to azilsartan through a hydrolysis process that occurs in the gastrointestinal tract and liver.

The antagonistic activity of azilsartan is demonstrated by its ability to inhibit angiotensin II-induced responses. Specifically, it reduces the angiotensin II-induced accumulation of inositol-1-phosphate in COS-7 cells that express recombinant human AT1 receptors, with an IC50 value of 2.6 nM. This indicates that azilsartan not only blocks the receptor but also prevents the signaling pathways initiated by angiotensin II.

Chemical properties

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The Uses of Azilsartan

Azilsartan is an analgesic and antiinflammatory drugs containing angiotensin II antagonists.

The Uses of Azilsartan

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 medication that functions as a potent angiotensin II blocker, specifically targeting the type 1 angiotensin II receptors. This higher potency and slower off-rate kinetics of azilsartan contribute to its enhanced effectiveness in lowering blood pressure compared to other drugs in its class.

The drug was first approved and launched in Japan for the treatment of arterial hypertension in May 2012. It is marketed under the trade name Azilva?. Notably, azilsartan was discovered and developed by Takeda, a pharmaceutical company with a history of innovation in this field. Takeda is also responsible for the development and launch of a prodrug form of azilsartan, known as azilsartan kamedoxomil or Edarbi?, which was introduced to the market in 2010.

The development of azilsartan and its prodrug represents a significant advancement in the treatment of hypertension, offering patients a more effective option for managing their blood pressure.

Synthesis

The most likely process-scale synthetic route likely mimics that which is disclosed in Takeda?ˉs 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.