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Vibegron (also known as KRP-114V; MK-4618; trade name Gemtesa) is a novel and potent β3 adrenergic receptor agonist approved in 2020 for the treatment of overactive bladder, which is a condition in which the bladder muscles contract uncontrollably and cause frequent urination.
| ln Vivo |
A dose-dependent reduction in micturition pressure and an increase in functional bladder capacity are observed with vitegron (1~12 μM; iv) [3]. Vibegron (30 mg/kg; oral; 4 weeks) increases the levels of TGF-β1, HIF-1α, and collagen type 1 and type 3 mRNA [4]. When compared to oxo-M untreated rats (intravesical instillation of vehicle), bebegron (1 and 10 mg/kg; i.v.; 30 min apart) significantly reduces bladder capacity in oxo-M treated rats [5].
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| Animal Protocol |
Animal/Disease Models: Rat
Doses: 1~12 μM Route of Administration: intravenous (iv) (iv)injection Experimental Results: Demonstrated dose-dependent decrease in micturition pressure and increase in functional bladder capacity. Animal/Disease Models: Female C57BL/6N mice (9 weeks old) Doses: 30 mg/kg Route of Administration: Po; 4-week Experimental Results: mRNA levels of type 1, type 3 collagen, TGF-β1 and HIF-1α at 4 weeks Upregulated. Animal/Disease Models: Female F344 rats (120–160 g) Doses: 1 and 10 mg/kg Route of Administration: intravenously (iv) (iv)(iv); 30 min intervals Experimental Results: vs. oxo-M untreated rats (intravesical instillation of vehicle) In comparison, Vibegron (10 mg/kg) Dramatically diminished bladder capacity in oxo-M-treated rats. |
| ADME/Pharmacokinetics |
Absorption, Distribution and Excretion
The mean time to peak concentration (Tmax) is 1–3 hours. Steady-state plasma concentrations are reached within 7 days after once-daily dosing. In a study of radiolabeled drugs, approximately 59% of the radiolabeled dose was recovered in feces, of which 54% was unmetabolized parent drug. Approximately 20% of the radioactivity was recovered in urine, of which 19% was unmetabolized parent drug. The mean apparent volume of distribution is 6304 liters. The mean plasma concentration to blood plasma concentration ratio is 0.9. Based on animal tissue distribution studies, vilbergerone does not cross the blood-brain barrier, suggesting a limited potential risk of central nervous system toxicity in humans. Limited information is available regarding the clearance rate of vilbergerone. Metabolism/Metabolites In vitro studies have shown that CYP3A4 is the major enzyme in the metabolism of vilbergerone, but plays a minor role in its clearance. The two main metabolic pathways are oxidation and glucuronidation, which produce two oxidative metabolites and three glucuronide metabolites, respectively. These metabolites are not fully elucidated. Biological Half-Life The terminal plasma half-life is 60 to 70 hours, and the effective half-life is 30.8 hours. |
| Toxicity/Toxicokinetics |
Hepatotoxicity
Vibergron, like other β-adrenergic drugs, rarely causes elevations in serum ALT or alkaline phosphatase. In large, randomized, placebo-controlled trials, the incidence of elevated serum transaminases was less than 1% in treated subjects, similar to patients receiving placebo and control drugs such as tolterodine. No clinically manifested liver injury has been reported in vibergron's registration trials or after its approval and wider use. Probability score: E (unlikely to cause clinically manifested liver injury). Protein Binding Vibergron binds to human plasma proteins in 49.6%–51.3% of cases. |
| References |
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| Additional Infomation |
Pharmacodynamics
Vibergron exhibits a selectivity for β3-adrenergic receptors that is more than 9000 times higher than that for β1AR or β2AR. Vibergron improves the clinical symptoms of overactive bladder by increasing bladder capacity without affecting bladder contraction. It significantly increases functional bladder capacity in a dose-dependent manner, thereby prolonging the voiding interval. In clinical studies, vilbergron inhibits detrusor muscle contraction in a concentration-dependent manner, reduces voiding pressure, and increases bladder compliance. In a Japanese clinical study of patients with overactive bladder, vilbergron significantly improved voiding frequency, urgency, and the number of urge incontinence episodes. |
| Molecular Formula |
C26H28N4O3
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|---|---|
| Molecular Weight |
444.535
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| Exact Mass |
444.216
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| CAS # |
1190389-15-1
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| PubChem CID |
44472635
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| Appearance |
White to off-white solid powder
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| Density |
1.4±0.1 g/cm3
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| Index of Refraction |
1.698
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| LogP |
0.66
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| Hydrogen Bond Donor Count |
3
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| Hydrogen Bond Acceptor Count |
5
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| Rotatable Bond Count |
6
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| Heavy Atom Count |
33
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| Complexity |
782
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| Defined Atom Stereocenter Count |
4
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| SMILES |
C1C[C@@H](N[C@@H]1CC2=CC=C(C=C2)NC(=O)[C@@H]3CCC4=NC=CC(=O)N34)[C@@H](C5=CC=CC=C5)O
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| InChi Key |
DJXRIQMCROIRCZ-XOEOCAAJSA-N
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| InChi Code |
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
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| Chemical Name |
(6S)-N-[4-[[(2S,5R)-5-[(R)-hydroxy(phenyl)methyl]pyrrolidin-2-yl]methyl]phenyl]-4-oxo-7,8-dihydro-6H-pyrrolo[1,2-a]pyrimidine-6-carboxamide
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| Synonyms |
MK4618KRP114VMK 4618 VIBEGRON KRP-114VUNII-M5TSE03W5U MK-4618 KRP 114V
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month Note: Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture and light. |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO : ~95 mg/mL (~213.71 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 4.75 mg/mL (10.69 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 47.5 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: 4.75 mg/mL (10.69 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 47.5 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 4.75 mg/mL (10.69 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.2495 mL | 11.2476 mL | 22.4952 mL | |
| 5 mM | 0.4499 mL | 2.2495 mL | 4.4990 mL | |
| 10 mM | 0.2250 mL | 1.1248 mL | 2.2495 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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