Description
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.
Originator
Takeda (United States)
Uses
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).
Definition
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.
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] CHRISTOPHER J FRENCH Burton E S A K M Tarikuz Zaman. The angiotensin receptor blocker, azilsartan medoxomil (TAK-491), suppresses vascular wall expression of plasminogen activator inhibitor type-I protein potentially facilitating the stabilization of atherosclerotic plaques.[J]. Journal of Cardiovascular Pharmacology, 2011, 58 2: 143-148. DOI:
10.1097/fjc.0b013e31821dcbea[2] KEIJI KUSUMOTO . Antihypertensive, insulin-sensitising and renoprotective effects of a novel, potent and long-acting angiotensin II type 1 receptor blocker, azilsartan medoxomil, in rat and dog models[J]. European journal of pharmacology, 2011, 669 1: Pages 84-93. DOI:
10.1016/j.ejphar.2011.07.014
