Mirabegron

Description

Betanis (Mirabegron) was approved in July 2011 by the Japanese Ministry of Health, Labour, and Welfare for the treatment of urgency, urinary frequency, and urinary urge urinary incontinence associated with overactive bladder (OAB). Mirabegron is synthesized by coupling 4-nitrophenethyl amine to (R)-2-hydroxy-2-phenylacetic acid. The resulting amide is reduced to an amine. The nitro group is then reduced and the resulting aniline is coupled to 2-(2-aminothiazol-4-yl) acetic acid to give mirabegron. Mirabegron has an EC₅₀ of 22 nM (intrinsic activity=0.8) for β3-AR with no detectable activity for β1- andβ2-AR (EC₅₀>10,000 nM). In an anesthetized rat rhythmic bladder contraction model in which bladder contractions are induced by saline, mirabegron at 3 mg/kg iv decreased the frequency of rhythmic bladder contraction without suppressing contraction amplitude. These data suggest that the activation of β3-AR increases bladder capacity without influencing the frequency of bladder contraction.

Chemical Properties

White to Off-White Solid

Originator

Astellas Pharma Inc. (Japan)

Uses

A potent bladder relaxant compound

Uses

Mirabegron is a selective β3-adrenoceptor agonist with EC50 of 22.4 nM.

Uses

Potent bladder relaxant and reagent for diabetes remedy.;Labeled Mirabegron, intended for use as an internal standard for the quantification of Mirabegron by GC- or LC-mass spectrometry.

Definition

ChEBI: A monocarboxylic acid amide obtained by formal condensation of the carboxy group of 2-amino-1,3-thiazol-4-ylacetic acid with the anilino group of (1R)-2-{[2-(4-aminophenyl)ethyl]amino}-1-phenylethanol. Used for the treatment of overactive ladder syndrome.

brand name

Betanis

Clinical Use

Mirabegron is an orally active β3-adrenoceptor agonist currently in development by Astellas Pharma for the treatment of overactive bladder (OAB). The drug is a nanomolar EC50 antagonist against human β3-AR biochemical assays with good selectivity over b1- and β2-ARs. Mirabegron demonstrates a novel mechanism by targeting the β3-AR for bladder relaxation to help manage OAB symptoms such as increased urinary urgency and frequency and urgency incontinence. However, mirabegron is a cytochrome P450 2D6 inhibitor, and it raises a concern for drug–drug interaction with concomitant administration of other cytochrome P450 2D6 substrates.

Synthesis

The synthesis of mirabegron began with a condensation reaction between (R)-styrene oxide (182) and 4-nitrophenylethylamine (183) in refluxing isopropanol to yield corresponding aminoalcohol 184 in 22% yield. Aminoalcohol 184 was protected as its N-Boc derivative with t-butyl dicarbonate in THF in 96% yield, and this was followed by nitro group hydrogenative reduction with 10% Pd/C to give free amine 185 in 96% yield. Aniline 185 was coupled with 2-amino-4-thiazolyl acetic acid 186 in the presence of EDCI and HOBt to give amide 187 in 85% yield. Removal of the Boc group was affected with 4 N HCl solution in a 2:1 volume ratio in ethyl acetate to obtain mirabegron HCl in 52% yield. The HCl salt was neutralized with 1 N NaOH to deliver mirabegron (XVII).

Drug interactions

Potentially hazardous
interactions with other drugs None known

Metabolism

Metabolised via multiple pathways involving dealkylation, oxidation, (direct) glucuronidation, and amide hydrolysis. Renal elimination of mirabegron is primarily through active tubular secretion along with glomerular filtration.

storage

Store at -20°C