hTRPV4 (IC50 = 48 nM); rTRPV4 (IC50 = 133 nM), mTRPV4 (IC50 = 17 nM)[1]

HEI-OC1 cells cultivated with high glucose showed a substantial reduction in mRNA expression after treatment with HC-067047 (1 μM) for 24 hours [2]. Treating HEI-OC1 cells with HC-067047 (1 μM) for 24 hours resulted in a significant decrease in TRPV4 protein expression [2]. Cell proliferation is inhibited when HEI-OC1 cells are treated with HC-067047 (1 μM) for 48 hours [2]. Apoptosis is promoted by HC-067047 (1 μM; 48 hours; HEI-OC1 cells) treatment [2].

Treatment with HC-067047 (0-50 mg/kg; i.p.; for 30 min; cyclophosphamide-treated WT and Trpv4?/? mice, and naive WT mice) improves bladder capacity and decreases frequency of urination in WT mice with cystitis. Does HC-067047 not impair Trpv4's ability to operate as a bladder? //? mice [1].

RT-PCR[2]
Cell Types: HEI-OC1 Cell
Tested Concentrations: 1 µM
Incubation Duration: 24 hrs (hours)
Experimental Results: Significant reduction in mRNA expression.

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Western Blot Analysis [2]
Cell Types: HEI-OC1 Cell
Tested Concentrations: 1 µM
Incubation Duration: 24 hrs (hours)
Experimental Results: TRPV4 protein expression was Dramatically diminished.

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Cell proliferation assay[2]
Cell Types: HEI-OC1 Cell
Tested Concentrations: 1 µM
Incubation Duration: 48 hrs (hours)
Experimental Results: Cell proliferation was inhibited.

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Apoptosis analysis[2]
Cell Types: HEI-OC1 Cell
Tested Concentrations: 1 µM
Incubation Duration: 48 hrs (hours)
Experimental Results: Promoted apoptosis.

Animal/Disease Models: cyclophosphamide-treated WT and Trpv4−/− mice, and naive WT mice [1]
Doses: 0 mg/kg, 1 mg/kg, 10 mg/kg, 50 mg/kg
Route of Administration: intraperitoneal (ip) injection; intraperitoneal (ip) injection. 30 min
Experimental Results: Functional bladder capacity increased and micturition frequency diminished in WT mice with cystitis and did not affect bladder function in Trpv4−/− mice.

[1]. Inhibition of the cation channel TRPV4 improves bladder function in mice and rats with cyclophosphamide-induced cystitis.Proc Natl Acad Sci U S A. 2010 Nov 2;107(44):19084-9.

[2]. Decreased Expression of TRPV4 Channels in HEI-OC1 Cells Induced by High Glucose Is Associated with Hearing Impairment. Yonsei Med J. 2018 Nov;59(9):1131-1137.

Reduced functional bladder capacity and concomitant increased micturition frequency (pollakisuria) are common lower urinary tract symptoms associated with conditions such as cystitis, prostatic hyperplasia, neurological disease, and overactive bladder syndrome. These symptoms can profoundly affect the quality of life of afflicted individuals, but available pharmacological treatments are often unsatisfactory. Recent work has demonstrated that the cation channel TRPV4 is highly expressed in urothelial cells and plays a role in sensing the normal filling state of the bladder. In this article, we show that the development of cystitis-induced bladder dysfunction is strongly impaired in Trpv4(-/-) mice. Moreover, we describe HC-067047, a previously uncharacterized, potent, and selective TRPV4 antagonist that increases functional bladder capacity and reduces micturition frequency in WT mice and rats with cystitis. HC-067047 did not affect bladder function in Trpv4(-/-) mice, demonstrating that its in vivo effects are on target. These results indicate that TRPV4 antagonists may provide a promising means of treating bladder dysfunction.[1]

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Purpose: Previous reports have shown that hyperglycemia-induced inhibition of transient receptor potential vanilloid sub type 4 (TRPV4), a transient receptor potential ion channel, affects the severity of hearing impairment (HI). In this study, we explored the role of TRPV4 in HI using HEI-OC1 cells exposed to high glucose (HG). Materials and methods: HEI-OC1 cells were cultured in a HG environment (25 mM D-glucose) for 48 hours, and qRT-PCR and Western blotting were used to analyze the expression of TRPV4 at the mRNA and protein level. TRPV4 agonist (GSK1016790A) or antagonist (HC-067047) in cultured HEI-OC1 cells was used to obtain abnormal TRPV4 expression. Functional TRPV4 activity was assessed in cultured HEI-OC1 cells using the MTT assay and a cell death detection ELISA. Results: TRPV4 agonists exerted protective effects against HG-induced HI, as evidenced by increased MTT levels and inhibition of apoptosis in HEI-OC1 cells. TRPV4 overexpression significantly increased protein levels of phosphorylated p38 mitogen-activated protein kinase (p-p38 MAPK), while TRPV4 antagonists had the opposite effect. Our results indicated that TRPV4 is a hyperglycemia-related factor that can inhibit cell proliferation and promote cell apoptosis by activating the MAPK signaling pathway in HEI-OC1 cells. Conclusion: Our results show that the overexpression of TRPV4 can attenuate cell death in HEI-OC1 cells exposed to HG.[2]

C26H28F3N3O2

471.5242

471.213

C, 66.23; H, 5.99; F, 12.09; N, 8.91; O, 6.79

883031-03-6

1481646-76-7 (HCl)

2742550

White to off-white solid powder

5.778

1

6

7

34

650

0

NCZYSQOTAYFTNM-UHFFFAOYSA-N

InChI=1S/C26H28F3N3O2/c1-19-23(25(33)30-22-10-5-9-21(17-22)26(27,28)29)18-24(20-7-3-2-4-8-20)32(19)12-6-11-31-13-15-34-16-14-31/h2-5,7-10,17-18H,6,11-16H2,1H3,(H,30,33)

2-methyl-1-(3-morpholin-4-ylpropyl)-5-phenyl-N-[3-(trifluoromethyl)phenyl]pyrrole-3-carboxamide

HC067047; HC 067047; 883031-03-6; HC-067047; HC 067047; HC067047; 2-methyl-1-(3-morpholin-4-ylpropyl)-5-phenyl-N-[3-(trifluoromethyl)phenyl]pyrrole-3-carboxamide; 2-Methyl-1-[3-(4-morpholinyl)propyl]-5-phenyl-N-[3-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxamide; CHEMBL2133556; DTXSID70372463; HC-067047

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~50 mg/mL (~106.04 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (5.30 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.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (5.30 mM) (saturation unknown) 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.
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 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.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (5.30 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.

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 (Please use freshly prepared in vivo formulations for optimal results.)