On June 28 2012, the FDA approved Mirabegron (tradename: Myrbetriq; Research Code: YM-178), a novel, first-in-class selective β3-adrenergic receptor agonist indicated for the treatment of overactive bladder (OAB) with symptoms of urge urinary incontinence, urgency, and urinary frequency. OAB syndrome is a urological condiction defined as urinary urgency, usually accompanied by frequency and nocturia, with or without urge urinary incontinence, in the absence of urinary tract infection or other obvious pathology. Mirabegron acts by relaxing the detrusor smooth muscle during the storage phase of the urinary bladder fill-void cycle by activation of β3-receptor which in turn increases bladder capacity.
Other treatments for OAB are already in the market and these include treatments with antimuscarinic drugs, such as Flavoxate (approved in 1970; tradename: Urispas; ChEMBL: CHEMBL1493), Oxybutynin (approved in 1975, tradenames: Ditropan, Ditropan XL, Oxytrol, Gelnique, Anturol; ChEMBL: CHEMBL1231), Tolterodine (approved in 1998; tradenames: Detrol, Detrol LA; ChEMBL: CHEMBL1382), Trospium (approved in 2004; tradenames: Santura, Santura XR; ChEMBL: CHEMBL1201344), Solifenacin (approved in 2004; tradenames: Vesicare; ChEMBL: CHEMBL1200803), Darifenacin (approved in 2004; tradenames: Enablex; ChEMBL: CHEMBL1346) and Fesoterodine (approved in 2008; tradenames: Toviaz; ChEMBL: CHEMBL1201764). While these drugs act by inhibiting the muscarinic action of acethylcholine, Mirabegron represents the first β3-receptor agonist to ever reach the market.
β3-receptor (ChEMBL: CHEMBL246; Uniprot: P13945) is a 408 amino-acid long G protein-coupled receptor (GPCR), belonging to Rhodopsin family (PFAM: PF00001; subfamily A17). Crystal structures of the closely related β1- and β2-receptors are known and act as good frameworks for understanding the mode of action of Mirabegron.
Mirabegron is a synthetic chiral small-molecule, with a molecular weight of 396.51 Da, a AlogP of 2.26, 4 hydrogen bond donors and 5 hydrogen bond acceptors, and thus fully rule-of-five compliant. (IUPAC: 2-(2-amino-1,3-thiazol-4-yl)-N-[4-[2-[[(2R)-2-hydroxy-2-phenylethyl]amino]ethyl]phenyl]acetamide; Canonical Smiles: C1=CC=C(C=C1)[C@H](CNCCC2=CC=C(C=C2)NC(=O)CC3=CSC(=N3)N)O; InChI: InChI=1S/C21H24N4O2S/c22-21-25-18(14-28-21)12-20(27)24-17-8-6-15(7-9-17)10-11-23-13-19(26)16-4-2-1-3-5-16/h1-9,14,19,23,26H,10-13H2,(H2,22,25)(H,24,27)/t19-/m0/s1)
The recommended starting dosage of Mirabegron is 25 mg once daily, with or without food, and is effective for 8 weeks. Depending individual patient efficacy and tolerability, the dose may be increased to 50 mg once daily.
Mirabegron has a bioavalibity of 29% at a dose of 25 mg, which increases to 35% at a dose of 50 mg, a volume of distribution (Vd) of approximately 1670 L and a moderate plasma protein binding of ca. 71%. Mirabegron is metabolized via multiple pathways involving dealkylation, oxidation, glucuronidation and amide hydrolyis. Studies have suggested that although CYP3A4 and CYP2D6 isoenzymes play a role in the oxidative metabolism of Mirabegron, this is a limited role in the overall elimination. In addition to these isoenzymes, the metabolism of Mirabegron may also involve butylcholinesterase, uridine diphospho-glucuronosyltransferases and alcohol dehydrogenase. Two major inactive metabolites were observed in human plasma and these represent 16% and 11% of the total exposure. Mirabegron total clearance (CLtot) from plasma is ca. 57 L/h, with a terminal half-life of approximately of 50 hours. Renal clearance (CLR) is approximately 13 L/h, which corresponds to nearly 25% of CLtot. The urinary elimination of unchanged Mirabegron is dose-dependent and ranges from ca. 6% after a daily dose of 25 mg to 12.2% after a daily dose of 100 mg.
The license holder is Astellas Pharma Inc. and the full prescribing information of Mirabegron can be found here.
Other treatments for OAB are already in the market and these include treatments with antimuscarinic drugs, such as Flavoxate (approved in 1970; tradename: Urispas; ChEMBL: CHEMBL1493), Oxybutynin (approved in 1975, tradenames: Ditropan, Ditropan XL, Oxytrol, Gelnique, Anturol; ChEMBL: CHEMBL1231), Tolterodine (approved in 1998; tradenames: Detrol, Detrol LA; ChEMBL: CHEMBL1382), Trospium (approved in 2004; tradenames: Santura, Santura XR; ChEMBL: CHEMBL1201344), Solifenacin (approved in 2004; tradenames: Vesicare; ChEMBL: CHEMBL1200803), Darifenacin (approved in 2004; tradenames: Enablex; ChEMBL: CHEMBL1346) and Fesoterodine (approved in 2008; tradenames: Toviaz; ChEMBL: CHEMBL1201764). While these drugs act by inhibiting the muscarinic action of acethylcholine, Mirabegron represents the first β3-receptor agonist to ever reach the market.
β3-receptor (ChEMBL: CHEMBL246; Uniprot: P13945) is a 408 amino-acid long G protein-coupled receptor (GPCR), belonging to Rhodopsin family (PFAM: PF00001; subfamily A17). Crystal structures of the closely related β1- and β2-receptors are known and act as good frameworks for understanding the mode of action of Mirabegron.
>ADRB3_HUMAN Beta-3 adrenergic receptor MAPWPHENSSLAPWPDLPTLAPNTANTSGLPGVPWEAALAGALLALAVLATVGGNLLVIV AIAWTPRLQTMTNVFVTSLAAADLVMGLLVVPPAATLALTGHWPLGATGCELWTSVDVLC VTASIETLCALAVDRYLAVTNPLRYGALVTKRCARTAVVLVWVVSAAVSFAPIMSQWWRV GADAEAQRCHSNPRCCAFASNMPYVLLSSSVSFYLPLLVMLFVYARVFVVATRQLRLLRG ELGRFPPEESPPAPSRSLAPAPVGTCAPPEGVPACGRRPARLLPLREHRALCTLGLIMGT FTLCWLPFFLANVLRALGGPSLVPGPAFLALNWLGYANSAFNPLIYCRSPDFRSAFRRLL CRCGRRLPPEPCAAARPALFPSGVPAARSSPAQPRLCQRLDGASWGVS
Mirabegron is a synthetic chiral small-molecule, with a molecular weight of 396.51 Da, a AlogP of 2.26, 4 hydrogen bond donors and 5 hydrogen bond acceptors, and thus fully rule-of-five compliant. (IUPAC: 2-(2-amino-1,3-thiazol-4-yl)-N-[4-[2-[[(2R)-2-hydroxy-2-phenylethyl]amino]ethyl]phenyl]acetamide; Canonical Smiles: C1=CC=C(C=C1)[C@H](CNCCC2=CC=C(C=C2)NC(=O)CC3=CSC(=N3)N)O; InChI: InChI=1S/C21H24N4O2S/c22-21-25-18(14-28-21)12-20(27)24-17-8-6-15(7-9-17)10-11-23-13-19(26)16-4-2-1-3-5-16/h1-9,14,19,23,26H,10-13H2,(H2,22,25)(H,24,27)/t19-/m0/s1)
The recommended starting dosage of Mirabegron is 25 mg once daily, with or without food, and is effective for 8 weeks. Depending individual patient efficacy and tolerability, the dose may be increased to 50 mg once daily.
Mirabegron has a bioavalibity of 29% at a dose of 25 mg, which increases to 35% at a dose of 50 mg, a volume of distribution (Vd) of approximately 1670 L and a moderate plasma protein binding of ca. 71%. Mirabegron is metabolized via multiple pathways involving dealkylation, oxidation, glucuronidation and amide hydrolyis. Studies have suggested that although CYP3A4 and CYP2D6 isoenzymes play a role in the oxidative metabolism of Mirabegron, this is a limited role in the overall elimination. In addition to these isoenzymes, the metabolism of Mirabegron may also involve butylcholinesterase, uridine diphospho-glucuronosyltransferases and alcohol dehydrogenase. Two major inactive metabolites were observed in human plasma and these represent 16% and 11% of the total exposure. Mirabegron total clearance (CLtot) from plasma is ca. 57 L/h, with a terminal half-life of approximately of 50 hours. Renal clearance (CLR) is approximately 13 L/h, which corresponds to nearly 25% of CLtot. The urinary elimination of unchanged Mirabegron is dose-dependent and ranges from ca. 6% after a daily dose of 25 mg to 12.2% after a daily dose of 100 mg.
The license holder is Astellas Pharma Inc. and the full prescribing information of Mirabegron can be found here.
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