| Size | Price | Stock | Qty |
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| 5mg |
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| Targets |
Velusetrag targets the serotonin 5-HT4 receptor (5-HT4R), a G-protein coupled receptor predominantly located in the enteric nervous system of the gastrointestinal wall. It binds with high affinity (pKi of 7.7) and has no affinity for 5-HT2A and 5-HT2B receptors (Ki > 10 μM), demonstrating its high selectivity. It is >500-fold selective for 5-HT4 over other 5-HT receptor types.
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| ln Vitro |
HEK-293 cells transfected with the h5-HT4(c) receptor exhibit a concentration-dependent rise in cAMP in response to velusetrag (10 pM-100 μM), with a pEC50 of 8.3 [1]. The guinea pig colonic longitudinal muscle/myenteric plexus (LMMP) contracts in response to velusetrag (100 pM-1 μM) in a concentration-dependent manner, with a pEC50 of 7.9 [1]. With a pEC50 of 7.9, velusetrag (0.001-10 μM) causes concentration-dependent relaxation of rat esophageal precontraction caused by carbachol (3 μM) [1].
In vitro, Velusetrag is a potent 5-HT4 receptor agonist, with an EC50 of 12.6 nM for inducing contraction in guinea pig colonic longitudinal muscle/myenteric plexus preparations. It shows high selectivity and high intrinsic activity at the 5-HT4 receptor. |
| ln Vivo |
In PD mice, a single intraperitoneal injection of velusetrag (3 mg/kg) greatly enhances the facilitation of contextual fear extinction [3]. Mice treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) exhibit an increase in cAMP levels in the hippocampus when administered with velusetrag (3 mg/kg) intraperitoneally [3]. In guinea pigs, velusetrag (0.003-3 mg/kg; single subcutaneous injection) shortens the time needed for dye excretion and accelerates intestinal transit in a dose-dependent manner [2]. In line with esophageal relaxation in rats, velusetrag (0.003–1 mg/kg; single intravenous administration) dose-dependently increases intercrystalline distance [2].
In vivo, Velusetrag has demonstrated prokinetic effects in animal models of gastrointestinal dysmotility. It has achieved proof-of-concept in patients with chronic idiopathic constipation. Its ability to enhance gastrointestinal motility makes it a candidate for treating various GI disorders. |
| Enzyme Assay |
In vitro enzyme/receptor binding (non-cell) assays for Velusetrag are performed using membrane preparations from cells expressing the human 5-HT4 receptor. These membranes are incubated with a radiolabeled 5-HT4 ligand, such as [³H]GR113808, and varying concentrations of Velusetrag. Binding affinity (Ki or pKi) is determined by competitive displacement of the radiolabeled ligand. Selectivity is assessed against other 5-HT receptors.
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| Cell Assay |
In vitro cell-based experiments for Velusetrag are conducted using cells expressing the human 5-HT4 receptor (e.g., HEK-293 or CHO cells). Cells are seeded in plates and loaded with a cAMP-sensitive dye or reporter gene. They are then treated with Velusetrag at various concentrations. The accumulation of cAMP is measured as a readout of 5-HT4 receptor activation, and the EC50 is calculated from the dose-response curve.
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| Animal Protocol |
Animal/Disease Models: Male C57BL/6 mice (7-8 weeks old) were injected with MPTP[3].
Doses: 3 mg/kg. Route of Administration: single ip. Experimental Results: Improved facilitation of contextual fear extinction. There was no improvement in impaired rotarod performance in PD mice. In vivo animal experiments for Velusetrag are performed in animal models of GI dysmotility (e.g., post-operative ileus, opioid-induced constipation). Velusetrag is administered orally. Gastrointestinal transit, gastric emptying, and colonic motility are assessed to evaluate its prokinetic efficacy. |
| ADME/Pharmacokinetics |
Velusetrag is orally bioavailable with good systemic exposure. It has a favorable pharmacokinetic profile with a half-life suitable for once-daily dosing. Detailed PK parameters are available from clinical trials.
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| Toxicity/Toxicokinetics |
Velusetrag is well-tolerated in clinical trials with a favorable safety profile. No significant cardiac (QTc prolongation) or serotonergic side effects have been reported at therapeutic doses due to its high selectivity.
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| References |
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| Additional Infomation |
Velusetrag is currently in clinical trials for the treatment of gastroparesis and Alzheimer's disease. It is a highly selective serotonin receptor agonist effective in patients with chronic constipation. The drug was developed by Theravance Medical Systems. Theravance discovered Velusetrag using its multivalent drug design technology in its research program dedicated to finding new treatments for gastrointestinal motility disorders.
Mechanism of Action Velusetrag is a potent, highly selective agonist with high intrinsic activity against the 5-HT4 receptor. Compared to other 5-HT receptor types, Velusetrag exhibits more than 500 times higher binding selectivity to the human 5-HT4 receptor. Theravance anticipates that Velusetrag's high selectivity makes it a potentially more effective and safer treatment for severe constipation and irritable bowel syndrome (IBS) that may be predominantly constipation-related. Pharmacodynamics Preclinical studies in vivo at Velusetrag showed that the compound exhibited potent 5-HT4 receptor agonist activity via multiple routes of administration, including oral administration, and provided strong prokinetic effects in the digestive tracts of three different animals, consistent with its highly efficient and selective in vitro 5-HT4 receptor agonist properties. Velusetrag is also known as TD-5108. It was being developed for GI motility disorders. Clinical trials were conducted for chronic constipation, gastroparesis, and Alzheimer's disease but were discontinued. |
| Molecular Formula |
C25H36N4O5S
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|---|---|
| Molecular Weight |
504.646
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| Exact Mass |
504.241
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| CAS # |
866933-46-2
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| Related CAS # |
Velusetrag hydrochloride;866933-51-9
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| PubChem CID |
11842633
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| Appearance |
White to off-white solid powder
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| Density |
1.34g/cm3
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| LogP |
3.153
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
7
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| Rotatable Bond Count |
8
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| Heavy Atom Count |
35
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| Complexity |
932
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| Defined Atom Stereocenter Count |
3
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| SMILES |
CC(C)N1C2=CC=CC=C2C=C(C1=O)C(=O)NC3C[C@H]4CC[C@@H](C3)N4C[C@H](CN(C)S(=O)(=O)C)O
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| InChi Key |
HXLOHDZQBKCUCR-FNNAPWSISA-N
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| InChi Code |
InChI=1S/C25H36N4O5S/c1-16(2)29-23-8-6-5-7-17(23)11-22(25(29)32)24(31)26-18-12-19-9-10-20(13-18)28(19)15-21(30)14-27(3)35(4,33)34/h5-8,11,16,18-21,30H,9-10,12-15H2,1-4H3,(H,26,31)/t18?,19?,20?,21-/m0/s1
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| Chemical Name |
N-(8-((R)-2-hydroxy-3-(N-methylmethylsulfonamido)propyl)-8-azabicyclo[3.2.1]octan-3-yl)-1-isopropyl-2-oxo-1,2-dihydroquinoline-3-carboxamide
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| Synonyms |
TD-5108 TD 5108 TD5108 Velusetrag
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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 : ~100 mg/mL (~198.16 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 5.75 mg/mL (11.39 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 57.5 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. Solubility in Formulation 2: ≥ 5.48 mg/mL (10.86 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 54.8 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. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.9816 mL | 9.9079 mL | 19.8157 mL | |
| 5 mM | 0.3963 mL | 1.9816 mL | 3.9631 mL | |
| 10 mM | 0.1982 mL | 0.9908 mL | 1.9816 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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