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Purity: ≥98%
Piboserod (SB 207266; trade name Serlipet) is a novel, potent and selective 5-HT(4) receptor antagonist marketed by GSK. It is applied in the treatment of irritable bowel syndrome and atrial fibrillation. A clinical phase II study was completed in 2007 by the Norwegian company Bio-Medisinsk Innovasjon AS (BMI) to examine the impact of piboserod in patients suffering from chronic heart failure.
| Targets |
5-HT4 Receptor
Piboserod is a potent, selective, orally active, and long-acting antagonist of the 5-HT4 serotonin receptor. [2] |
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| ln Vitro |
Piboserod (SB 207266) is a selective 5-HT(4) receptor antagonist, at inhibiting the 5-HT(4)-mediated potentiating effect of serotonin (5-HT) on the neurally-mediated contractile responses of human detrusor strips to electrical field stimulations (EFS). [1]
Strips of human detrusor muscle were mounted in Krebs-HEPES buffer under a resting tension of 500 mg and EFS (20 Hz, 1 ms duration at 300 mA for 5 s) was applied continuously at 1 min intervals. After stabilization of the EFS-induced contractions, concentration-response curves to 5-HT (0.1 nM-100 microM) were constructed in the absence or presence of 1 or 100 nM of piboserod. [1] Piboserod did not modify the basal contractions but concentration-dependently antagonized the ability of 5-HT to enhance bladder strip contractions to EFS. In presence of 1 and 100 nM of piboserod, the maximal 5-HT-induced potentiations were reduced to 45.0+/-7.9 and 38.7+/-8.7%, respectively. A mean apparent antagonist dissociation constant value (K(B)) of 0.56+/-0.09 nM was determined. These data show the ability of piboserod to antagonize with high potency the enhancing properties of 5-HT on neurally-mediated contractions of isolated human bladder strips. [1] |
| ln Vivo |
In a prospective, double-blind, parallel-group clinical trial involving patients with symptomatic heart failure (NYHA class II-IV, LVEF ≤0.35), treatment with Piboserod (80 mg once daily for 24 weeks, on top of standard heart failure therapy) significantly increased left ventricular ejection fraction (LVEF) by 1.7% (CI 0.3, 3.2, P=0.020) compared to placebo. This improvement was primarily driven by a reduction in end-systolic volume. [2]
In a small subset of patients not on chronic β-blocker therapy (n=19), there was a trend toward a greater increase in LVEF (2.7%, CI -1.1, 6.6, P=0.15) with Piboserod. [2] Treatment with Piboserod did not result in significant changes in secondary efficacy parameters compared to placebo, including N-terminal pro-brain natriuretic peptide (NT-proBNP) levels, norepinephrine, aldosterone, quality of life (Minnesota Living with Heart Failure questionnaire scores), or exercise tolerance (6-minute walk test distance). [2] |
| Toxicity/Toxicokinetics |
In this clinical trial, the frequency of adverse event reports was higher in the Piboserod group (n=67) than in the placebo group (n=70). Common adverse events (incidence >5%) in the Piboserod group included constipation (13.4%), dizziness (13.4%), fatigue (13.4%), dyspnea (16.4%), musculoskeletal symptoms (17.9%), and respiratory infection (14.9%). Laboratory results showed elevated serum creatinine (10.4%) and elevated serum potassium (6.0%). [2] The Piboserod group had a higher incidence of serious adverse events (22 adverse events in 17 patients) compared to the placebo group (7 adverse events in 5 patients). Three deaths occurred in the Piboserod group (two due to end-stage heart failure and one due to cancer complicated by sepsis), while no deaths occurred in the placebo group, but a causal relationship with the drug has not been established. [2] Previous human studies have shown that doses of Piboserod exceeding 80 mg can prolong the QT interval by 2-3%, but no arrhythmic effects have been reported. In this trial, the mean QTc interval did not change significantly from baseline to the end of the study in either the Piboserod or placebo group. [2]
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| References |
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| Additional Infomation |
Piboserod (SB 207266) is a selective 5-HT(4) receptor antagonist.
Drug Indications For the treatment of atrial fibrillation and irritable bowel syndrome (IBS). Mechanism of Action Piboserod appears to be a specific antagonist of the 5-HT4 receptor, one of the serotonin receptors. At least in animal studies, 5-HT4 receptor antagonists have been shown to antagonize serotonin-induced peristaltic reflexes and 5-HT-induced defecation. Because 5-HT4 receptors are present in human atrial cells, and stimulation of these receptors can lead to atrial arrhythmias, Piboserod has been used in clinical trials for the treatment of atrial fibrillation. Pharmacodynamics GlaxoSmithKline investigated Piboserod (a 5-HT4 receptor antagonist) for the treatment of atrial fibrillation. A Phase II clinical trial of the drug was underway in March 2004, but development was terminated in December of the same year. Previously, pibolone was used to treat irritable bowel syndrome (IBS), but development for this indication was terminated in 1999. |
| Molecular Formula |
C22H31N3O2
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|---|---|
| Molecular Weight |
369.50044
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| Exact Mass |
369.242
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| Elemental Analysis |
C, 71.51; H, 8.46; N, 11.37; O, 8.66
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| CAS # |
152811-62-6
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| Related CAS # |
Piboserod hydrochloride; 178273-87-5
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| PubChem CID |
177336
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| Appearance |
White to off-white solid powder
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| LogP |
3.994
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
3
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| Rotatable Bond Count |
6
|
| Heavy Atom Count |
27
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| Complexity |
492
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| Defined Atom Stereocenter Count |
0
|
| SMILES |
O=C(C1=C(OCCC2)N2C3=C1C=CC=C3)NCC4CCN(CCCC)CC4
|
| InChi Key |
KVCSJPATKXABRQ-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C22H31N3O2/c1-2-3-11-24-13-9-17(10-14-24)16-23-21(26)20-18-7-4-5-8-19(18)25-12-6-15-27-22(20)25/h4-5,7-8,17H,2-3,6,9-16H2,1H3,(H,23,26)
|
| Chemical Name |
N-[(1-butylpiperidin-4-yl)methyl]-3,4-dihydro-2H-[1,3]oxazino[3,2-a]indole-10-carboxamide
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| Synonyms |
Piboserod; SB-207266; SB 207266; SB207266; trade name: Serlipet
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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 |
| 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: ~25 mg/mL (~67.7 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (6.77 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 25.0 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: ≥ 2.5 mg/mL (6.77 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (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 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.7064 mL | 13.5318 mL | 27.0636 mL | |
| 5 mM | 0.5413 mL | 2.7064 mL | 5.4127 mL | |
| 10 mM | 0.2706 mL | 1.3532 mL | 2.7064 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.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT00421746 | Completed | Drug: Piboserod | Congestive Heart Failure | Bio-Medisinsk Innovasjon | January 2006 | Phase 2 |
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