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Purity: ≥98%
BFH772 (also known as BFH-772) is a novel and potent orally bioavailable VEGFR2 inhibitor that targets VEGFR2 kinase with IC50 of 3 nM. Although BFH772 lost 500-fold potency on FLK-1, FLT-1, and FLT-4, it was very effective at targeting VEGFR2 kinase. Targeting B-RAF, RET, and TIE-2, BFH772 was at least 40 times less potent than the other two compounds. The ligand-induced autophosphorylation of PDGFR, KIT, and RET kinases was inhibited by BFH772. BFH772 exhibited selectivity towards the kinases that encode EGFR, ERBB2, INS-R, and IGF-1R, as well as the cytoplasmic BCR-ABL kinase.
| Targets |
VEGFR2 (IC50 = 3 nM)
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| ln Vitro |
BFH772 was 500 times less potent on FLK-1, FLT-1, and FLT-4, but it was very effective at targeting VEGFR2 kinase (IC50 value of 3 nM). With at least 40-fold reduced potency, BFH772 was highly selective against B-RAF, RET, and TIE-2 in addition to VEGFR2. With IC50 values ranging between 30 and 160 nM, BFH772 inhibits the ligand-induced autophosphorylation of RET, PDGFR, and KIT kinases[1].
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| ln Vivo |
BFH772 all potently inhibited the growth of melanoma (by 54−90% for the primary tumor and 71−96% for metastasis growth) when given orally once daily at a dose of 3 mg/kg[1].
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| Enzyme Assay |
BFH772 is extremely selective; it targets B-RAF, RET, and TIE-2, though at least 40 times less potently, in addition to inhibiting VEGFR2 at 3 nM IC50. When tested against all other tyrosine- and serine/threonine-specific protein kinases, BFH772 is inactive (IC50>10 μM; >2 μM for cKIT). With an IC50 of 4.6±0.6 nM in CHO cells, BFH772 inhibits VEGFR2. With an IC50 of 3 nM, BFH772 inhibits VEGFR2 in HUVEC cells. The ligand-induced autophosphorylation of RET, PDGFR, and KIT kinases is inhibited by BFH772, with IC50 values ranging from 30 to 160 nM. The cytoplasmic BCR-ABL kinase and the kinases of EGFR, ERBB2, INS-R, and IGF-1R are the only targets of BFH772's selective activity (IC50 values >0.5 μM). BFH772's IC50 (<0.01 nM, n=2) shows that, at remarkably low nM concentrations, they abolished VEGF-induced proliferation.
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| Cell Assay |
The 96-well plates were used to incubate subconfluent HUVECs in triplicate using a basal medium that contained 1.5% FCS and a constant concentration of either VEGF (10 ng/mL), bFGF (0.5 ng/mL), or FCS (5%) with or without compounds. The cells were incubated for a further twenty-four hours after the addition of the BrdUrd labeling solution. This was followed by the fixation, blocking, and addition of the peroxidase-labeled anti-BrdUrd antibody. Then, at 450 nm, bound antibody was found using spectrophotometry.
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| Animal Protocol |
Mice: Groups of six female FVB mice, weighing between 18 and 20 g, are kept in the housing. Mice (n = 6 per group) have subcutaneous implants of porous chambers containing VEGF (2 μg/mL) in 0.5 mL of 0.8% w/v agar (containing heparin, 20 U/mL). The vascularized tissue that surrounds the chamber grows as a result of VEGF. The tissue's weight and TIE-2 levels can be used to quantify this dose-dependent response. The mice are given oral treatment once a day for four days, beginning 4-6 hours prior to chamber implantation, with compounds or a vehicle (PEG200 100%, 5 mL/kg). Twenty-four hours after the last dose, the animals are killed in order to measure the vascularized tissues. After determining the tissue weight, a lysate is made ready for TIE-2 ELISA analysis.
Rats: For compounds 4, 9, and 10, catheters are implanted in the jugular vein and femoral artery of female Sprague-Dawley rats, or in the femoral artery and vein of naïve female rats strain OFA for BFH772 and BAW2881. Throughout the experiment, animals are kept in single cages with unrestricted access to food and water, and they are given 96 hours to recuperate. Injections into the femoral vein of female OFA rats were given either 1 mg/kg of BFH772 dissolved in N-methyl pyrrolidone/polyethylene glycol200 (30:70, v/v) or 2.5 mg/kg of BAW2881 dissolved in ethanol/dimethylisosorbide/polyethylene glycol400/D5W (10/15/35/40 v/v). 5% glucose/water (v/v) is D5W. Oral administration: Female OFA rats are gavaged with a dose of 25 mg/kg for BAW2881 or 3 mg/kg for BFH772, which are prepared as a micronized suspension (dissolved/suspended in 0.5% carboxymethyl cellulose in distilled water) (n = 4 rats per group). Following an intravenous dose of 3 mg/kg for compounds 4, 9, and 10, formulated in ethanol/NMP/polyethylene glycol400/D5W (10/10/50/30) (n = 2 rats per group), or a suspension in 0.5% carboxymethyl cellulose in distilled water dosed at 50 mg/kg (n = 3 rats per group), were administered to female Sprague-Dawley rats at 8 weeks of age. Blood samples are drawn into heparinized tubes at the scheduled times, and HPLC/MS-MS is used to measure the compound content of the plasma. |
| References | |
| Additional Infomation |
BFH772 is under investigation in clinical trial NCT01449591 (Safety, Tolerability and Efficacy of BFH772 in Rosacea Patients).
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| Molecular Formula |
C23H16F3N3O3
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| Molecular Weight |
439.39
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| Exact Mass |
439.114
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| Elemental Analysis |
62.87; H, 3.67; F, 12.97; N, 9.56; O, 10.92
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| CAS # |
890128-81-1
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| Related CAS # |
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| PubChem CID |
24756034
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| Appearance |
White to off-white solid powder
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| Density |
1.4±0.1 g/cm3
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| Boiling Point |
541.2±50.0 °C at 760 mmHg
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| Flash Point |
281.1±30.1 °C
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| Vapour Pressure |
0.0±1.5 mmHg at 25°C
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| Index of Refraction |
1.656
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| LogP |
4.37
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
8
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| Rotatable Bond Count |
5
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| Heavy Atom Count |
32
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| Complexity |
635
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| Defined Atom Stereocenter Count |
0
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| SMILES |
O=C(C1C2C(=CC(=CC=2)OC2C=C(CO)N=CN=2)C=CC=1)NC1C=C(C(F)(F)F)C=CC=1
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| InChi Key |
JNLSTLQFDDAULK-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C23H16F3N3O3/c24-23(25,26)15-4-2-5-16(10-15)29-22(31)20-6-1-3-14-9-18(7-8-19(14)20)32-21-11-17(12-30)27-13-28-21/h1-11,13,30H,12H2,(H,29,31)
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| Chemical Name |
6-[6-(hydroxymethyl)pyrimidin-4-yl]oxy-N-[3-(trifluoromethyl)phenyl]naphthalene-1-carboxamide
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| Synonyms |
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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 |
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| 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) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (5.69 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. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.2759 mL | 11.3794 mL | 22.7588 mL | |
| 5 mM | 0.4552 mL | 2.2759 mL | 4.5518 mL | |
| 10 mM | 0.2276 mL | 1.1379 mL | 2.2759 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.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT01449591 | Completed | Drug: BFH772 1% ointment Drug: Vehicle ointment |
Erythemato-telangiectatic Rosacea | Novartis Pharmaceuticals | September 2011 | Phase 2 |
| NCT04098692 | Completed | Drug: BFH772 Drug: Placebo |
Psoriasis Arthritis |
Novartis Pharmaceuticals | September 2009 | Phase 1 Phase 2 |
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