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Purity: ≥98%
GSK2193874 (GSK-2193874) is a novel, potent, orally bioactive, and selective TRPV4 (Transient Receptor Potential Vanilloid 4) antagonist with the potential to be used for congestive heart failure. It inhibits TRPV4 with IC50 of 2 nM and 40 nM for rTRPV4 and hTRPV4. GSK2193874 was identified as a selective, orally active TRPV4 blocker that inhibits Ca(2+) influx through recombinant TRPV4 channels and native endothelial TRPV4 currents. In isolated rodent and canine lungs, TRPV4 blockade prevented the increased vascular permeability and resultant pulmonary edema associated with elevated PVP. Furthermore, in both acute and chronic HF models, GSK2193874 pretreatment inhibited the formation of pulmonary edema and enhanced arterial oxygenation. Finally, GSK2193874 treatment resolved pulmonary edema already established by myocardial infarction in mice. These findings identify a crucial role for TRPV4 in the formation of HF-induced pulmonary edema and suggest that TRPV4 blockade is a potential therapeutic strategy for HF patients.
| ln Vitro |
GSK2193874 selectively targets TRPV1, TRPA1, TRPC3, TRPC6, and TRPM8 (IC50>25 μM) and targets the TRP channel [1]. GSK2193874 is an oral TRPV4 blocker that functions as a selective inhibitor of Ca2+ influx through the inhibition of both native endothelium TRPV4 currents and recombinant TRPV4 channels. GSK2193874 suppressed the activation of recombinant TRPV4 currents in whole-cell patch-clamp tests when added to external solutions at concentrations of 3 nM and above. However, GSK2193874 is ineffective up to 10 μM when delivered inside cells via inclusion in intracellular pipette solutions [2].
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| ln Vivo |
After evaluating GSK2193874's pharmacokinetic (PK) properties in rats and dogs, it was discovered that these animals' half-lives and oral exposures were appropriate for oral administration in chronic animal models (rat PK: iv CL=7.3 mL/min/kg, po t1/2=10 hours, %F=31; dog PK: intravenous injection CL=6.9 mL/min/kg, oral t1/2=31 hours, %F=53). Furthermore, at doses up to 30 mg/kg, GSK2193874 had no effect on rats' heart rates or blood pressure. An oral bioavailable TRPV4 inhibitor that is first-in-class, GSK2193874 has been shown to enhance lung function in a number of heart failure animals [1]. In rats, GSK2193874 exhibits good oral bioavailability (31%) and low clearance (7.3 mL/min/kg) [2].
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| References |
[1]. Cheung M, et al. Discovery of GSK2193874: An Orally Active, Potent, and Selective Blocker of Transient Receptor Potential Vanilloid 4. ACS Med Chem Lett. 2017 Mar 20;8(5):549-554.
[2]. Thorneloe KS, et al. An orally active TRPV4 channel blocker prevents and resolves pulmonary edema induced by heart failure. Sci Transl Med. 2012 Nov 7;4(159):159ra148 |
| Molecular Formula |
C37H38BRF3N4O
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|---|---|
| Molecular Weight |
691.6230
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| CAS # |
1336960-13-4
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| SMILES |
O=C(C1=C(CN2CCC(N3CCCCC3)CC2)C(C4=CC=CC(C(F)(F)F)=C4)=NC5=CC(Br)=CC=C15)NC6(C7=CC=CC=C7)CC6
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| InChi Key |
UIVOZBSCHXCGPS-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C37H38BrF3N4O/c38-28-12-13-30-32(23-28)42-34(25-8-7-11-27(22-25)37(39,40)41)31(24-44-20-14-29(15-21-44)45-18-5-2-6-19-45)33(30)35(46)43-36(16-17-36)26-9-3-1-4-10-26/h1,3-4,7-13,22-23,29H,2,5-6,14-21,24H2,(H,43,46)
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| Chemical Name |
7-bromo-N-(1-phenylcyclopropyl)-3-[(4-piperidin-1-ylpiperidin-1-yl) methyl]-2-[3-(trifluoromethyl)phenyl]quinoline-4-carboxamide
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| Synonyms |
GSK2193874; GSK2193874A; GSK 2193874; GSK 2193874A; GSK-2193874; GSK-2193874A
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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 (~144.59 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: 2.5 mg/mL (3.61 mM) in 5% DMSO + 95% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with sonication.
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. Solubility in Formulation 2: ≥ 2.08 mg/mL (3.01 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 20.8 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. View More
Solubility in Formulation 3: ≥ 2.08 mg/mL (3.01 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 | 1.4459 mL | 7.2294 mL | 14.4588 mL | |
| 5 mM | 0.2892 mL | 1.4459 mL | 2.8918 mL | |
| 10 mM | 0.1446 mL | 0.7229 mL | 1.4459 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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