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GSK2193874

MCE China：GSK2193874

Brand：MedChemExpress (MCE)

Cat. No.HY-100720

CAS：1336960-13-4

Purity：99.91%

Storage：Powder -20°C 3 years 4°C 2 years In solvent -80°C 2 years -20°C 1 year

Shipping：Room temperature in continental US; may vary elsewhere.

Description：GSK2193874 is an orally active, potent, and selective TRPV4 antagonist with IC50s of 2 nM and 40 nM for rTRPV4 and hTRPV4.

In Vitro：GSK2193874 is profiled against TRP channels and is selective against TRPV1, TRPA1, TRPC3, TRPC6, and TRPM8 (IC50>25 μM)[1]. GSK2193874 is a selective, orally active TRPV4 blocker that inhibits Ca2+ influx through recombinant TRPV4 channels and native endothelial TRPV4 currents. In whole-cell patch-clamp studies, GSK2193874 inhibits activation of recombinant TRPV4 currents when applied to the extracellular solution at 3 nM and above but is ineffective at up to 10 μM when applied to the inside of the cell by inclusion in the intracellular pipette solution[2].

In Vivo：The pharmacokinetic (PK) properties for GSK2193874 are evaluated in both rat and dog and found to have half-lives and oral exposure suitable for oral dosing in chronic animal models (Rat PK: iv CL=7.3 mL/min/kg, po t1/2=10 h, %F=31. Dog PK: iv CL=6.9 mL/min/kg, po t1/2=31 h, %F=53). In addition, GSK2193874 shows no blood pressure or heart rate effect in rats when dose up to 30 mg/kg. GSK2193874 is the first-in-class orally bioavailable TRPV4 inhibitor that demonstrated ability to improve pulmonary functions in a number of heart failure models[1]. GSK2193874 shows low clearance (7.3 mL/min/kg) and good rat oral bioavailability (31%)[2].

Animal Administration：Rats[2] Adult male Sprague-Dawley rats (n=7 to 8 per group) are treated with vehicle (6% Cavitron) or GSK2193874 (30 mg/kg per day) via oral gavage for at least 4 days before osmotic challenges. Rats undergo acute and chronic hyper- and hypo-osmotic challenges. Sprague-Dawley rats are administered vehicle (0.9% NaCl, 25 mL/kg), NSC 269420 (30 mg/kg), or hydrochlorothiazide (30 mg/kg) via oral gavage. Urine is then collected over 4 hours followed by blood sampling. Rats recover for 4 days and then receive GSK2193874 (30 mg/kg per day oral gavage) for 5 days before repeating the diuretic challenge.

IC50 & Target：IC50: 2 nM (rTRPV4), 40 nM (hTRPV4)[1] Cellular Effect Cell Line Type Value Description References

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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.  [Content Brief]

[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.  [Content Brief]