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Bazedoxifene HCl 198480-56-7

Bazedoxifene HCl 198480-56-7

CAS No.: 198480-56-7

Bazedoxifene HCl (formerly TSE-424; WAY-140424; WAY140424; TSE424; Viviant), the hydrochloride salt of Bazedoxifene, is
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Bazedoxifene HCl (formerly TSE-424; WAY-140424; WAY140424; TSE424; Viviant), the hydrochloride salt of Bazedoxifene, is a non-steroidal, indole-based and 3rd generation selective estrogen receptor modulator (SERM) with potential antineoplastic activity. It inhibits ERα and ERβ with IC50s of 23 nM and 89 nM, respectively. Bazedoxifene was approved by FDA in 2013 as part of the combination drug Duavee used for the prevention of postmenopausal osteoporosis.


Physicochemical Properties


Molecular Formula C30H34N2O3.HCL
Molecular Weight 507.06
Exact Mass 506.234
CAS # 198480-56-7
Related CAS # Bazedoxifene;198481-32-2;Bazedoxifene acetate;198481-33-3
PubChem CID 9936012
Appearance Typically exists as solid at room temperature
LogP 7.07
Hydrogen Bond Donor Count 3
Hydrogen Bond Acceptor Count 4
Rotatable Bond Count 7
Heavy Atom Count 36
Complexity 623
Defined Atom Stereocenter Count 0
SMILES

CC1=C(C2=CC=C(C=C2)O)N(CC3=CC=C(C=C3)OCCN4CCCCCC4)C5=C1C=C(C=C5)O.Cl

InChi Key COOWZQXURKSOKE-UHFFFAOYSA-N
InChi Code

InChI=1S/C30H34N2O3.ClH/c1-22-28-20-26(34)12-15-29(28)32(30(22)24-8-10-25(33)11-9-24)21-23-6-13-27(14-7-23)35-19-18-31-16-4-2-3-5-17-31;/h6-15,20,33-34H,2-5,16-19,21H2,1H3;1H
Chemical Name

1-(4-(2-(azepan-1-yl)ethoxy)benzyl)-2-(4-hydroxyphenyl)-3-methyl-1H-indol-5-ol hydrochloride
Synonyms

TSE-424; WAY-140424; TSE 424; PF-05208749 HCl; 1-[[4-[2-(azepan-1-yl)ethoxy]phenyl]methyl]-2-(4-hydroxyphenyl)-3-methylindol-5-ol;hydrochloride; WAY140424; WAY 140424; TSE424; Viviant.
HS Tariff Code 2934.99.9001
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)

Biological Activity


Targets ERα (IC50 = 26 nM); ERβ (IC50 = 99 nM)[1]
ln Vitro Small-molecule GP130 inhibitor benzedoxifene hydrochloride interacts to the GP130 D1 domain[1]. In the GP130/STAT3 pathway signaling, benzodiazepine hydrochloride suppresses the phosphorylation of STAT3 that is triggered by IL-6 and IL-11[1]. In human pancreatic cancer cells, benzodiazepine hydrochloride (10 μM–20 μM; 2 hours) suppresses the phosphorylation of STAT3 caused by cytokines[2]. Bazedoxifene hydrochloride (5–20 μM; given overnight) causes human pancreatic cancer cells to undergo apoptosis[2]. IL-6-induced STAT3 nuclear translocation is inhibited by benzedoxifene hydrochloride[2]. By inhibiting GP130, benzedoxifene hydrochloride prevents pancreatic cancer cells from migrating[2].
ln Vivo In a mouse model, benzodiazepine hydrochloride (5 mg/kg; ir; daily; for 18 days) suppresses the formation of Capan-1 tumors in vivo[2].
Enzyme Assay Ligand binding[1]
Interaction of bazedoxifene acetate (BZA) with human ERα and ERβ was assessed with a solid phase competitive radioligand binding assay using [3H]-17β- estradiol as previously described.
STAT3 DNA binding assay[2]
BxPC-3 cells were seeded in a 10-cm plate and treated with Bazedoxifene (5–10 μmol/L) or DMSO for 24 hours. The Nuclear Extract Kit was used to prepare cell nuclear extracts following the manufacturer's protocol. Nuclear extracts were analyzed for STAT3 DNA–binding activity using a STAT3 DNA binding ELISA kit (Active Motif) with an ELISA-based method. Absorbance was read at 450 nm.
STATs phosphorylation induced by cytokines or growth factors[2]
PANC-1, AsPC-1, and HPAF-II pancreatic cancer cells were seeded in 10-cm plates and allowed to adhere overnight. The following night, the cells were serum starved. The cells were then left untreated or were treated with Bazedoxifene (5–20 μmol/L) or DMSO. After 2 hours, the untreated and Bazedoxifene-treated cells were stimulated by IL6 (50 ng/mL), IL11 (50 ng/mL), OSM (50 ng/mL), or INFγ (50 ng/mL) for 30 minutes. The cells were harvested and analyzed by Western blot analysis for p-STAT3Y705 or p-STAT1Y701.
Cell Assay Western Blot Analysis[2]
Cell Types: AsPC-1 cells
Tested Concentrations: 10 μM, 20 μM
Incubation Duration: 2 hrs (hours)
Experimental Results: Inhibited IL-6, IL-11 or OSM (50 ng/mL) induced STAT3 phosphorylation.

Apoptosis Analysis[2]
Cell Types: Capan-1 cells, BxPC-3 cells, HPAF-II cells, HPAC cells
Tested Concentrations: 10 μM, 20 μM (Capan-1); 5 μM, 10 μM (BxPC-3); 10 μM, 20 μM (HPAF-II); 10 μM, 15 μM (HPAC)
Incubation Duration: Overnight
Experimental Results: Induced apoptosis.
Animal Protocol Animal/Disease Models: 6weeks old female athymic nude mice[2]
Doses: 5 mg /kg
Route of Administration: po (oral gavage), daily, for 18 days
Experimental Results: Suppressed pancreatic cancer xenograft tumor growth and induced apoptosis in tumor cells.
Vasomotor instability (hot flush)[1]
Ovariectomized female (60 d) rats were obtained after surgery. The surgeries were performed minimally 7 d before initiation of any experiment. Vehicle and ethinyl estradiol (0.3 mg/kg) were included in each replicate. Bazedoxifene was administered orally in a saline, Tween-80, methylcellulose vehicle. A detailed description of methodology for evaluating vasomotor instability in rats has been published (21). Briefly, compound treatment (17β-estradiol, ethinyl estradiol, or bazedoxifene) is initiated, and on the third day of treatment each animal receives a morphine pellet sc. This is followed by two more pellets on the fifth day of treatment. On the eighth day, a thermistor is taped to the animal’s tail to measure tail skin temperature for 15 min (to obtain baseline temperature) followed by a sc injection of naloxone (1 mg/kg). Tail skin temperature readings continue for 1 h after naloxone injection.
Capan-1 (3 × 106) and HPAF-II (3 × 106) cells in Matrigel were injected subcutaneously into the both side of flank area of 6-week-old female athymic nude mice. After Capan-1 tumor development, which was 1 week after initial implantation, mice were divided into two treatment groups consisting of four mice (tumors: n = 8): DMSO vehicle control and gavage injection of Bazedoxifene (5 mg/kg/d). Mice bearing HPAF-II tumor were irrigated with Bazedoxifene(5 mg/kg/d) and/or injected via abdomen with paclitaxel (15 mg/kg, 2/w). Tumor growth was determined by measured the length (L) and width (W) of the tumor every other day with a caliper, and tumor volume was calculated on the basis of the following formula: volume = 0.52 × LW2. After 21 days of treatment, tumors were harvested, snap-frozen in dry ice, and stored at −80°C. Tumors tissue homogenates were lysed and separated by SDS-PAGE to examine the expression of STAT3 phosphorylation, P-ERK1/2, P-AKT (Ser473), and cleaved caspase-3.[2]
References

[1]. Bazedoxifene acetate: a selective estrogen receptor modulator with improved selectivity. Endocrinology. 2005 Sep;146(9):3999-4008.

[2]. Bazedoxifene as a Novel GP130 Inhibitor for Pancreatic Cancer Therapy. Mol Cancer Ther. 2016 Nov; 15(11): 2609–2619.

Additional Infomation The IL6/GP130/STAT3 pathway is crucial for tumorigenesis in multiple cancer types, including pancreatic cancer, and presents as a viable target for cancer therapy. We reported Bazedoxifene, which is approved as a selective estrogen modulator by FDA, as a novel inhibitor of IL6/GP130 protein-protein interactions using multiple ligand simultaneous docking and drug repositioning approaches. STAT3 is one of the major downstream effectors of IL6/GP130. Here, we observed Bazedoxifene inhibited STAT3 phosphorylation and STAT3 DNA binding, induced apoptosis, and suppressed tumor growth in pancreatic cancer cells with persistent IL6/GP130/STAT3 signaling in vitro and in vivo In addition, IL6, but not INFγ, rescued Bazedoxifene-mediated reduction of cell viability. Bazedoxifene also inhibited STAT3 phosphorylation induced by IL6 and IL11, but not by OSM or STAT1 phosphorylation induced by INFγ in pancreatic cancer cells, suggesting that Bazedoxifene inhibits the GP130/STAT3 pathway mediated by IL6 and IL11. Furthermore, Bazedoxifene combined with paclitaxel or gemcitabine synergistically inhibited cell viability and cell migration in pancreatic cancer cells. These results indicate that Bazedoxifene is a potential agent and can generate synergism when combined with conventional chemotherapy in human pancreatic cancer cells and tumor xenograft in mice. Therefore, our results support that Bazedoxifene as a novel inhibitor of GP130 signaling and may be a potential and safe therapeutic agent for human pancreatic cancer therapy. [2]

Solubility Data


Solubility (In Vitro)
DMSO:101 mg/mL (199.2 mM)
Water:<1 mg/mL
Ethanol:<1 mg/mL
Solubility (In Vivo) Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

Injection Formulations
(e.g. IP/IV/IM/SC)
Injection Formulation 1: DMSO : Tween 80: Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution 50 μL Tween 80 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 :Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO 400 μLPEG300 50 μL Tween 80 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO 900 μL (20% SBE-β-CD in saline)]
*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.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO 100 μLPEG300 200 μL castor oil 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10: 10 : 80 (i.e. 100 μL Ethanol 100 μL Cremophor 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300:Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH 400 μLPEG300 50 μL Tween 80 450 μL Saline)

Oral Formulations Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).
Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

 (Please use freshly prepared in vivo formulations for optimal results.)
Preparing Stock Solutions 1 mg 5 mg 10 mg
1 mM 1.9722 mL 9.8608 mL 19.7215 mL
5 mM 0.3944 mL 1.9722 mL 3.9443 mL
10 mM 0.1972 mL 0.9861 mL 1.9722 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.