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Purity: ≥98%
BI-749327 (BI749327) is a novel, potent and orally bioavailable antagonist of Transient receptor potential canonical type 6 (TRPC6) with the potential to be used for treating PAH (pulmonary arterial hypertension) and PH (pulmonary hypertension) due to respiratory diseases or hypoxemia. It inhibits TRPC6 with an IC50 of 13 nM in mice. BI-749327 exhibits 85- and 42-fold selectivity over the most closely related channels, TRPC3 and TRPC7. TRPC6 calcium conductance results in the stimulation of nuclear factor of activated T cells (NFAT) that triggers pathological cardiac and renal fibrosis and disease. BI 749327 suppresses NFAT activation in HEK293T cells expressing wild-type or gain-of-function TRPC6 mutants (P112Q, M132T, R175Q, R895C, and R895L) and blocks associated signaling and expression of prohypertrophic genes in isolated myocytes. In vivo, BI 749327 (30 mg/kg/day, yielding unbound trough plasma concentration ∼180 nM) improves left heart function, reduces volume/mass ratio, and blunts expression of profibrotic genes and interstitial fibrosis in mice subjected to sustained pressure overload. Additionally, BI 749327 dose dependently reduces renal fibrosis and associated gene expression in mice with unilateral ureteral obstruction. These results provide in vivo evidence of therapeutic efficacy for a selective pharmacological TRPC6 inhibitor with oral bioavailability and suitable pharmacokinetics to ameliorate cardiac and renal stress-induced disease with fibrosis.
| ln Vitro |
In HEK293T cells expressing wild-type or gain-of-function TRPC6 mutants, BI-749327 reduces NFAT activation. It also prevents associated signaling and the production of pro-hypertrophic genes in isolated myocytes [1].
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| ln Vivo |
BI-749327 (30 mg/kg/day; ig) improves left ventricular function, decreases volume/mass ratio, and attenuates the expression of profibrotic genes and interstitial fibrosis in mice with chronic pressure overload [1]. BI-749327 dose-dependently decreases renal fibrosis and associated gene expression in mice with unilateral ureteral obstruction [1]. BI-749327 has a lengthy terminal half-life (t1/2 8.5-13.5 hours) in mice (3-30 mg/kg; oral) [1].
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| Animal Protocol |
Animal/Disease Models: C57BL/6J mice[1]
Doses: 30 mg/kg/day Route of Administration: po (oral gavage) Experimental Results: The left ventricular function of mice under sustained stress was improved, the volume/mass ratio was diminished, and profibrotic genes and interstitial fibrosis expression attenuated by overload. Animal/Disease Models: CD-1 mice[1] Doses: 3 mg/kg, 10 mg/kg, 30 mg/kg Route of Administration: Oral Experimental Results: t1/2 8.5-13.5 hrs (hrs (hours)) |
| References |
[1]. Lin B L, et al. In vivo selective inhibition of TRPC6 by antagonist BI 749327 ameliorates fibrosis and dysfunction in cardiac and renal disease. Proc Natl Acad Sci U S A. 2019 May 14;116(20):10156-10161.
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| Molecular Formula |
C23H21F3N4O2
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|---|---|
| Molecular Weight |
442.433655500412
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| CAS # |
2361241-23-6
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| SMILES |
NC1=NN=C(C2CCN(C(C3=CC=C(OC4=CC=C(C(F)(F)F)C=C4)C=C3)=O)CC2)C=C1
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| Synonyms |
BI749327; BI 749327; BI-749327
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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 : ~31.25 mg/mL (~70.63 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (4.70 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. Solubility in Formulation 2: ≥ 2.08 mg/mL (4.70 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 20.8 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. View More
Solubility in Formulation 3: ≥ 2.08 mg/mL (4.70 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 | 2.2602 mL | 11.3012 mL | 22.6024 mL | |
| 5 mM | 0.4520 mL | 2.2602 mL | 4.5205 mL | |
| 10 mM | 0.2260 mL | 1.1301 mL | 2.2602 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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