Vibegron

Identification

Name

Vibegron

Accession Number

DB14895

Description

Vibegron is a potent, selective beta-3 adrenergic receptor (β3) agonist that relaxes the detrusor smooth muscle of the bladder, thereby increasing bladder capacity.⁶ Vibegron was first approved in Japan in September 2018 for the treatment of overactive bladder,¹ a condition associated with distressing symptoms of urge urinary incontinence, urgency, and urinary frequency, and reduced quality of life of patients. On December 23, 2020, vibegron was approved for the same indication in adults. It is available as oral tablets under the market name GEMTESA.⁷

Vibegron is the second beta-3 adrenergic agonist approved for the treatment of overactive bladder following mirabegron, which was approved in 2012. Unlike mirabegron, vibegron is less likely to be associated with drug-drug interactions involving the CYP3A4, 2D6, or 2C9 enzymes.⁴

Type

Small Molecule

Groups

Approved, Investigational

Structure

3D

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MOLSDF3D-SDFPDBSMILESInChI

Similar Structures

Structure for Vibegron (DB14895)

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Weight

Average: 444.535
Monoisotopic: 444.216140778

Chemical Formula

C₂₆H₂₈N₄O₃

Synonyms

• Vibegron
• Vibégron
• Vibegrón
• Vibegronum

External IDs

• KRP-114V
• MK 4618

Pharmacology

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Indication

Vibegron is indicated for the treatment of overactive bladder (OAB) with symptoms of urge urinary incontinence, urgency, and urinary frequency in adults.⁶

Associated Conditions

• Urinary Bladder, Overactive

Contraindications & Blackbox Warnings

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Pharmacodynamics

Vibegron selectivity for beta-3 adrenergic receptors is >9000 times higher than for β1AR or β2AR.⁴ Vibegron improves clinical symptoms of overactive bladder by increasing bladder capacity without affecting bladder contraction.³ It significantly increases the functional bladder volume in a dose-dependent manner, which results in prolongation of the interval between voids. In clinical studies, vibegron inhibited detrusor bladder contractions in a concentration-dependent manner, reduced voiding pressure, and increased bladder compliance.⁴ In Japanese clinical studies comprising patients with overactive bladder, vibegron significantly improved the frequency of micturition, urgency, and urgency incontinence episodes.^2,4

Mechanism of action

Overactive bladder is characterized by symptoms of urge urinary incontinence, urgency, and urinary frequency. Bladder filling and emptying are regulated by the coordinated communication between sympathetic and parasympathetic systems. Bladder filling occurs via parasympathetic inhibition and the sympathetic hypogastric nerve releasing norepinephrine, which acts on beta-adrenergic receptors responsible for mediating detrusor muscle relaxation.^3,5 Symptoms of overactive bladder are thought to be caused by the deterioration of the sensory connections between the bladder, spinal cord and brain, leading to changes in the lower urinary tract and abnormal bladder sensations of the urge to void at small bladder volumes.⁴

Beta-3 adrenergic receptors (β3ARs) are expressed in the kidneys and lower urinary tract, including ureters, urethra, prostate, and bladder. Vibegron is a selective agonist at β3AR. One vibegron binds to the receptor, β3AR is stimulated and undergoes a conformation change and activates adenylyl cyclases (AC), which promotes the formation of cyclic adenosine monophosphate (cAMP). Increased intracellular cAMP concentration leads to the activation of cAMP-dependent protein kinase A (PKA), which subsequently phosphorylates myosin light chains that are responsible for inhibiting the interaction of actin with myosin dependent on calcium – calmodulin complex.^4,5 In clinical trials, vibegron increased cAMP levels in a dose-proportional manner. There is evidence that β3AR agonists may also work via sensory mechanisms without directly affecting detrusor muscle motor function.⁴

Target	Actions	Organism
ABeta-3 adrenergic receptor	agonist	Humans

Absorption

The mean T_max is 1-3 hours. Steady-state concentrations are achieved within 7 days of once-daily dosing.⁶

Volume of distribution

The mean apparent volume of distribution is 6304 L. The average blood-to-plasma concentration ratio is 0.9.⁶ According to tissue distribution studies in animals, vibegron does not penetrate the blood-brain barrier, suggesting limited potential for CNS toxicity in humans.⁴

Protein binding

Vibegron is 49.6–51.3% bound to human plasma proteins.⁴

Metabolism

In vitro, CYP3A4 is the main enzyme responsible for the metabolism of vibegron, which plays a minor role in the elimination of vibegron.⁶ Two predominant metabolic pathways are oxidation and glucuronidation to form two oxidative metabolites and three glucuronide metabolites.⁴ Metabolites have not been fully characterized.

Route of elimination

In a radiolabeled drug study, approximately 59% of the radiolabeled dose was recovered in feces, in which 54% of that amount was in the unchanged parent drug form. About 20% of the radioactivity was recovered in urine, in which 19% of the amount was in the unchanged form.⁶

Half-life

The terminal plasma half-life ranges from 60 to 70 hours.⁴ The effective half-life is 30.8 hours.⁶

Clearance

There is limited information on the clearance rate of vibegron.

Adverse Effects

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Toxicity

There is limited clinical information on overdose from vibegron. In the case of a suspected drug overdose, supportive and symptomatic treatment should be initiated.⁶

Affected organisms

• Humans and other mammals

Pathways

Not Available

Pharmacogenomic Effects/ADRs

Not Available

Interactions

Drug Interactions

This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.

• Approved
• Vet approved
• Nutraceutical
• Illicit
• Withdrawn
• Investigational
• Experimental
• All Drugs

Drug	Interaction
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Darifenacin	Darifenacin may increase the smooth muscle relaxing activities of Vibegron.
Digoxin	The serum concentration of Digoxin can be increased when it is combined with Vibegron.
Fesoterodine	Fesoterodine may increase the smooth muscle relaxing activities of Vibegron.
Flavoxate	Flavoxate may increase the smooth muscle relaxing activities of Vibegron.
Mirabegron	Mirabegron may increase the smooth muscle relaxing activities of Vibegron.
Oxybutynin	Oxybutynin may increase the smooth muscle relaxing activities of Vibegron.
Propiverine	Propiverine may increase the smooth muscle relaxing activities of Vibegron.
Solifenacin	Solifenacin may increase the smooth muscle relaxing activities of Vibegron.
Tolterodine	Tolterodine may increase the smooth muscle relaxing activities of Vibegron.
Trospium	Trospium may increase the smooth muscle relaxing activities of Vibegron.

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Food Interactions

• Take with or without food. A high-fat meal had no clinically significant effects on vibegron plasma concentrations.

Products

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International/Other Brands

Beova (Kyorin Pharmaceutical Co., Ltd)

Brand Name Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End	Region	Image
Gemtesa	Tablet, film coated	75 mg/1	Oral	Urovant Sciences, Inc.	2020-12-29	Not applicable

Categories

Drug Categories

• Cytochrome P-450 CYP3A Substrates
• Cytochrome P-450 CYP3A4 Substrates
• Cytochrome P-450 Substrates
• Drugs for Urinary Frequency and Incontinence
• Genitourinary Smooth Muscle Relaxants
• P-glycoprotein substrates
• Pyrimidines
• Selective Beta 3-adrenergic Agonists

Classification

Not classified

Chemical Identifiers

UNII

M5TSE03W5U

CAS number

1190389-15-1

InChI Key

DJXRIQMCROIRCZ-XOEOCAAJSA-N

InChI

InChI=1S/C26H28N4O3/c31-24-14-15-27-23-13-12-22(30(23)24)26(33)29-19-8-6-17(7-9-19)16-20-10-11-21(28-20)25(32)18-4-2-1-3-5-18/h1-9,14-15,20-22,25,28,32H,10-13,16H2,(H,29,33)/t20-,21+,22-,25+/m0/s1

IUPAC Name

(6S)-N-(4-{[(2S,5R)-5-[(R)-hydroxy(phenyl)methyl]pyrrolidin-2-yl]methyl}phenyl)-4-oxo-4H,6H,7H,8H-pyrrolo[1,2-a]pyrimidine-6-carboxamide

SMILES

[H][C@@]1(CC[C@@H](CC2=CC=C(NC(=O)[C@@H]3CCC4=NC=CC(=O)N34)C=C2)N1)[C@H](O)C1=CC=CC=C1

References

General References

1. Keam SJ: Vibegron: First Global Approval. Drugs. 2018 Nov;78(17):1835-1839. doi: 10.1007/s40265-018-1006-3. [PubMed:30411311]
2. Yoshida M, Takeda M, Gotoh M, Yokoyama O, Kakizaki H, Takahashi S, Masumori N, Nagai S, Minemura K: Efficacy of vibegron, a novel beta3-adrenoreceptor agonist, on severe urgency urinary incontinence related to overactive bladder: post hoc analysis of a randomized, placebo-controlled, double-blind, comparative phase 3 study. BJU Int. 2020 May;125(5):709-717. doi: 10.1111/bju.15020. Epub 2020 Feb 23. [PubMed:31991511]
3. Di Salvo J, Nagabukuro H, Wickham LA, Abbadie C, DeMartino JA, Fitzmaurice A, Gichuru L, Kulick A, Donnelly MJ, Jochnowitz N, Hurley AL, Pereira A, Sanfiz A, Veronin G, Villa K, Woods J, Zamlynny B, Zycband E, Salituro GM, Frenkl T, Weber AE, Edmondson SD, Struthers M: Pharmacological Characterization of a Novel Beta 3 Adrenergic Agonist, Vibegron: Evaluation of Antimuscarinic Receptor Selectivity for Combination Therapy for Overactive Bladder. J Pharmacol Exp Ther. 2017 Feb;360(2):346-355. doi: 10.1124/jpet.116.237313. Epub 2016 Dec 13. [PubMed:27965369]
4. Rechberger T, Wrobel A: Evaluating vibegron for the treatment of overactive bladder. Expert Opin Pharmacother. 2020 Sep 29:1-9. doi: 10.1080/14656566.2020.1809652. [PubMed:32993398]
5. Schena G, Caplan MJ: Everything You Always Wanted to Know about beta3-AR * (* But Were Afraid to Ask). Cells. 2019 Apr 16;8(4). pii: cells8040357. doi: 10.3390/cells8040357. [PubMed:30995798]
6. FDA Approved Drug Products: GEMTESA (vibegron) tablets, for oral use [Link]
7. Drugs.com: FDA Approves Gemtesa [Link]

External Links

KEGG Drug

D10433

ChemSpider

28528047

BindingDB

50146154

RxNav

2472254

ChEBI

142418

ChEMBL

CHEMBL2107826

ZINC

ZINC000084757336

Wikipedia

Vibegron

Clinical Trials

Clinical Trials

Phase	Status	Purpose	Conditions	Count
3	Completed	Treatment	Urinary Bladder, Overactive	2
3	Enrolling by Invitation	Treatment	Urinary Bladder, Overactive	1
3	Recruiting	Treatment	Urinary Bladder, Overactive	1
2	Completed	Treatment	Irritable Bowel Syndrome (IBS)	1
2	Completed	Treatment	Urinary Bladder, Overactive	1
1	Completed	Treatment	High Blood Pressure (Hypertension)	1
1	Completed	Treatment	Urinary Bladder, Overactive	2
1	Terminated	Treatment	Urinary Bladder, Overactive	1

Pharmacoeconomics

Manufacturers

Not Available

Packagers

Not Available

Dosage Forms

Form	Route	Strength
Tablet, film coated	Oral	75 mg/1

Prices

Not Available

Patents

Patent Number	Pediatric Extension	Approved	Expires (estimated)	Region
US8247415	No	2010-12-01	2030-12-01
US8653260	No	2009-04-02	2029-04-02

Properties

State

Solid

Experimental Properties

Not Available

Predicted Properties

Property	Value	Source
logP	2.38	ChemAxon
pKa (Strongest Acidic)	12.46	ChemAxon
pKa (Strongest Basic)	10.61	ChemAxon
Physiological Charge	1	ChemAxon
Hydrogen Acceptor Count	5	ChemAxon
Hydrogen Donor Count	3	ChemAxon
Polar Surface Area	94.03 Å2	ChemAxon
Rotatable Bond Count	6	ChemAxon
Refractivity	126.71 m3·mol-1	ChemAxon
Polarizability	47.17 Å3	ChemAxon
Number of Rings	5	ChemAxon
Bioavailability	1	ChemAxon
Rule of Five	Yes	ChemAxon
Ghose Filter	Yes	ChemAxon
Veber's Rule	No	ChemAxon
MDDR-like Rule	Yes	ChemAxon

Predicted ADMET Features

Not Available

Spectra

Mass Spec (NIST)

Not Available

Spectra

Not Available

Targets

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Details1. Beta-3 adrenergic receptor

Kind

Protein

Organism

Humans

Pharmacological action

Yes

Actions

Agonist

General Function

Protein homodimerization activity

Specific Function

Beta-adrenergic receptors mediate the catecholamine-induced activation of adenylate cyclase through the action of G proteins. Beta-3 is involved in the regulation of lipolysis and thermogenesis.

Gene Name

ADRB3

Uniprot ID

P13945

Uniprot Name

Beta-3 adrenergic receptor

Molecular Weight

43518.615 Da

References

1. Rechberger T, Wrobel A: Evaluating vibegron for the treatment of overactive bladder. Expert Opin Pharmacother. 2020 Sep 29:1-9. doi: 10.1080/14656566.2020.1809652. [PubMed:32993398]
2. FDA Approved Drug Products: GEMTESA (vibegron) tablets, for oral use [Link]

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Drug created on May 20, 2019 14:33 / Updated on February 21, 2021 18:55