MIRABEGRON

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C21H24N4O2S
Molecular Weight	396.506
Optical Activity	UNSPECIFIED
Defined Stereocenters	1 / 1
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

SMILES

NC1=NC(CC(=O)NC2=CC=C(CCNC[C@H](O)C3=CC=CC=C3)C=C2)=CS1

InChI

InChIKey=PBAPPPCECJKMCM-IBGZPJMESA-N

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

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Description

Mirabegron (trade name Myrbetriq in the US and Betmiga in Europe) is a drug for the treatment of overactive bladder (OAB). It was developed by Astellas Pharma and was approved in the United States in July 2012. Originally developed as a treatment for diabetes, the development of mirabegron was later refocused to OAB. Mirabegron is an orally bioavailable agonist of the human beta-3 adrenergic receptor (ADRB3), with muscle relaxing, neuroprotective and potential antineoplastic activities. Upon oral administration, mirabegron binds to and activates ADRB3, which leads to smooth muscle relaxation. Mirabegron also restores sympathetic stimulation in mesenchymal stem cell (MSC) niches, inhibits JAK2-mutated hematopoietic stem cell (HSC) expansion and blocks the progression of myeloproliferative neoplasms (MPNs). Lack of sympathetic stimulation of the MSC and HSC niche is associated with the development of MPNs.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Beta-3 adrenergic receptor 49	Agonist 2,678		22.4 nM [EC50]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Overactive bladder 38	Curative		Approved 8,429	MYRBETRIQ

C_max

Value	Dose	Co-administered	Analyte	Population
12.8 ng/mL	50 mg single, oral		MIRABEGRON plasma	Homo sapiens
29.4 ng/mL	50 mg single, oral		MIRABEGRON plasma	Homo sapiens

AUC

Value	Dose	Co-administered	Analyte	Population
177 ng × h/mL	50 mg single, oral		MIRABEGRON plasma	Homo sapiens
46.82 ng × h/mL	50 mg single, oral		MIRABEGRON plasma	Homo sapiens

T_1/2

Value	Dose	Co-administered	Analyte	Population
41.5 h	50 mg single, oral		MIRABEGRON plasma	Homo sapiens
28.1 h	50 mg single, oral		MIRABEGRON plasma	Homo sapiens

F_unbound

Value	Dose	Co-administered	Analyte	Population
29%	50 mg single, oral		MIRABEGRON plasma	Homo sapiens

Doses

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Dose	Population	Adverse events
200 mg 1 times / day multiple, oral Studied dose	healthy, 23.6 years (range: 20–27 years)	Other AEs: Pulse rate increased...
400 mg single, oral Highest studied dose	healthy, 23.8 years (range: 20–27 years)
200 mg 1 times / day multiple, oral Studied dose	unhealthy, 58.0±13.7 years	Other AEs: Cardiac disorders, Eye disorders...
25 mg 1 times / day steady, oral Recommended	unhealthy, adult	Disc. AE: Constipation, Hypertension...

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AEs

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AE	Significance	Dose	Population
Pulse rate increased	2%	200 mg 1 times / day multiple, oral Studied dose	healthy, 23.6 years (range: 20–27 years)
Constipation	1.8%	200 mg 1 times / day multiple, oral Studied dose	unhealthy, 58.0±13.7 years
Dyspepsia	2.4%	200 mg 1 times / day multiple, oral Studied dose	unhealthy, 58.0±13.7 years
Cardiac disorders	3%	200 mg 1 times / day multiple, oral Studied dose	unhealthy, 58.0±13.7 years
Eye disorders	3.6%	200 mg 1 times / day multiple, oral Studied dose	unhealthy, 58.0±13.7 years

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Overview

CYP3A4	CYP2C9	CYP2D6	hERG
substrate 1,737 inhibitor 1,587	inhibitor 1,767	substrate 1,217 inhibitor 1,852	inhibitor 1,612

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP1A2 1,524 CYP2B6 810 CYP2C8 911 CYP2C19 1,478 CYP2E1 882 P-gp 1,461 OCT1 512 OCT2 647	P-gp 1,537 UGT 192 BChE 1 OCT1 327 OCT2 355 OCT3 80 OATP1A2 62 OATP2B1 104 BCRP 561	CYP1A2 701 CYP3A 129

Drug as perpetrator

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Target	Modality	Activity	Clinical evidence
CYP2D6 1,891	inhibitor 3,277	moderate	yes (co-administration study)
CYP1A2 1,692	inducer 1,573	no
CYP3A 298	inducer 1,573	no
CYP1A2 1,692	inhibitor 3,277	unlikely
CYP2B6 1,001	inhibitor 3,277	unlikely

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Drug as victim

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Target	Modality	Activity	Clinical evidence
CYP3A4 1,737	substrate 3,367	major	yes (co-administration study)
BChE 1	substrate 3,367	minor
CYP2D6 1,217	substrate 3,367	minor
UGT 192	substrate 3,367	minor
BCRP 561	substrate 3,367	no

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Tox targets

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Target	Modality	Activity	Metabolite	Clinical evidence
hERG 1,647	inhibitor 1,626

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Sourcing

Sourcing

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Vendor/Aggregator	ID	URL
ChEBI	CHEBI:65349	https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:65349
MolPort	MolPort-019-994-262	https://www.molport.com/shop/molecule-link/MolPort-019-994-262
Selleck Chemicals	mirabegron-ym178	http://www.selleckchem.com/products/mirabegron-ym178.html
ZINC	ZINC000001996784	http://zinc15.docking.org/substances/ZINC000001996784

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PubMed

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Title	Date	PubMed
A quantitative analysis of mRNA expression of alpha 1 and beta-adrenoceptor subtypes and their functional roles in human normal and obstructed bladders.	2003 Aug	12853849
Systems pharmacological analysis of drugs inducing stevens-johnson syndrome and toxic epidermal necrolysis.	2015 May 18	25811541

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Patents

Sample Use Guides

In Vivo Use Guide

25 mg once daily, with or without food. 25 mg is effective within 8 weeks. Based on individual efficacy and tolerability, may increase dose to 50 mg once daily.

Route of Administration: Oral

In Vitro Use Guide

Mirabegron increased cAMP accumulation with EC(50) value = 19 nmol/L in CHO cells expressing rat β(3)-adrenoceptors.

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Name

Type

Language

MIRABEGRON

Official Name

English

MIRABEGRON [USAN]

Common Name