Acolbifene
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MedKoo CAT#: 204170

CAS#: 182167-02-8 (free base)

Description: Acolbifene, also known as EM-652, or SCH-57068, is a selective estrogen receptor modulator (SERM). Acolbifene is currently being studied in the prevention of breast cancer in women at high risk of breast cancer. EM-652 (SCH 57068) and the prodrug EM-800 (SCH57050) which are the most potent of the known antiestrogens. EM-652 is the compound having the highest affinity for the estrogen receptor, including estradiol. It has higher affinity for the ER than ICI 182780, hydroxytamoxifen, raloxifene, droloxifene and hydroxytoremifene. EM-652 has the most potent inhibitory activity on both ER alpha and ER beta compared to any of the other antiestrogens tested. EM-652 was also the most potent inhibitor of the percentage of cycling cancer cells. ( J Steroid Biochem Mol Biol. 1999 Apr-Jun;69(1-6):51-84.)


Chemical Structure

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Acolbifene
CAS# 182167-02-8 (free base)

Theoretical Analysis

MedKoo Cat#: 204170
Name: Acolbifene
CAS#: 182167-02-8 (free base)
Chemical Formula: C29H31NO4
Exact Mass: 457.22531
Molecular Weight: 457.56074
Elemental Analysis: C, 76.12; H, 6.83; N, 3.06; O, 13.99

Price and Availability

Size Price Availability Quantity
5.0mg USD 205.0 Same Day
10.0mg USD 350.0 Same Day
25.0mg USD 650.0 Same Day
50.0mg USD 850.0 Same Day
100.0mg USD 1450.0 Same Day
200.0mg USD 2450.0 Same Day
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Related CAS #: 182167-02-8 (free base)   252555-01-4 (HCl)  

Synonym: EM 652; EM-652; EM652; SCH57068; SCH-57068; SCH 57068; Acolbifene.

IUPAC/Chemical Name: (S)-3-(4-hydroxyphenyl)-4-methyl-2-(4-(2-(piperidin-1-yl)ethoxy)phenyl)-2H-chromen-7-ol

InChi Key: DUYNJNWVGIWJRI-LJAQVGFWSA-N

InChi Code: InChI=1S/C29H31NO4/c1-20-26-14-11-24(32)19-27(26)34-29(28(20)21-5-9-23(31)10-6-21)22-7-12-25(13-8-22)33-18-17-30-15-3-2-4-16-30/h5-14,19,29,31-32H,2-4,15-18H2,1H3/t29-/m0/s1

SMILES Code: OC1=CC2=C(C=C1)C(C)=C(C3=CC=C(O)C=C3)[C@H](C4=CC=C(OCCN5CCCCC5)C=C4)O2

Appearance: Yellow solid powder

Purity: >98% (or refer to the Certificate of Analysis)

Shipping Condition: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.

Storage Condition: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).

Solubility: Soluble in DMSO, not in water

Shelf Life: >2 years if stored properly

Drug Formulation: This drug may be formulated in DMSO

Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).

HS Tariff Code: 2934.99.9001

Biological target: Acolbifene (EM-652) is a selective estrogen receptor antagonist and an antiestrogen with an IC50 of 1.01 nM.
In vitro activity: EM-652 (acolbifene), which acts as a complete estrogen antagonist in the mammary gland and endometrium, exerts a typical estrogen-like effect on endothelial cells, triggering NO synthesis. EM-652 has a double mechanism of action, inducing a rapid nongenomic stimulation of eNOS activity as well as an up-regulation of eNOS protein upon longer exposure. Nongenomic signaling through ERs is of primary importance for estrogen action. This is true also in endothelial cells, where rapid NO synthesis upon exposure to estrogen relies on nongenomic activation of MAPK and PI3K pathways (13–15). EM-652-induced NO release by endothelial cells follows the same kinetic as natural estrogen. Upon challenge with EM-652, a biphasic increase in NO release from endothelial cells can be found; the first part (between 0 and 10 min) can be blocked by MAPK inhibitors, whereas the second (between 20 and 30 min) and more substantial part is sensitive to the presence of PI3K inhibitors. PI3K activation leads to the recruitment of Akt, which is responsible for the Ser/Thr phosphorylation and rapid activation of eNOS (28, 29). EM-652 triggers Akt activation in endothelial cells that is time-consistent with eNOS activation and that can be prevented by blocking ER signaling. It is possible that ER activation by EM-652 triggers the sequential recruitment of MAPK and PI3K/Akt pathways in human endothelial cells, leading to rapid nongenomic eNOS activation. Reference: Endocrinology. 2002 Jun;143(6):2052-61. https://academic.oup.com/endo/article/143/6/2052/2989418
In vivo activity: The selective estrogen receptor (ER) modulator (SERM) acolbifene (ACOL), a potent and pure antiestrogen in the mammary gland and uterus, exerts beneficial pro-estrogenic actions on energy balance, insulin sensitivity and lipid metabolism. ACOL binds ERs alpha and beta, both of which have been involved in the metabolic actions of estrogen. ACOL was administered for 4 weeks to male and female wild-type and ERalpha knockout (KO) mice, and indices of energy balance as well as plasma and liver lipid concentrations were determined. ERalpha KO mice were heavier, gained more fat mass and had larger adipose depots than their wild-type counterparts. In both genders, ACOL decreased fat gain (50%) and white adipose tissue mass in male and female wild-type, but not in ERalpha KO mice. ACOL reduced plasma cholesterol in female wild-type mice (-27%), whereas the compound remained ineffective in their ERalpha KO counterparts. Plasma triglycerides were unaffected by ACOL. Finally, ACOL decreased liver cholesterol and triglyceride concentrations only in wild-type female animals. The present data demonstrate that the marked ACOL-induced reduction in body fat accretion and cholesterolemia are entirely explained by its interaction with the ERα. Reference: Int J Obes (Lond). 2005 Oct;29(10):1236-44. https://www.nature.com/articles/0803014

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
DMSO 50.0 109.28

Preparing Stock Solutions

The following data is based on the product molecular weight 457.56074 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Recalculate based on batch purity %
Concentration / Solvent Volume / Mass 1 mg 5 mg 10 mg
1 mM 1.15 mL 5.76 mL 11.51 mL
5 mM 0.23 mL 1.15 mL 2.3 mL
10 mM 0.12 mL 0.58 mL 1.15 mL
50 mM 0.02 mL 0.12 mL 0.23 mL
Formulation protocol: 1. Simoncini T, Varone G, Fornari L, Mannella P, Luisi M, Labrie F, Genazzani AR. Genomic and nongenomic mechanisms of nitric oxide synthesis induction in human endothelial cells by a fourth-generation selective estrogen receptor modulator. Endocrinology. 2002 Jun;143(6):2052-61. doi: 10.1210/endo.143.6.8749. PMID: 12021169. 2. Lemieux C, Phaneuf D, Labrie F, Giguère V, Richard D, Deshaies Y. Estrogen receptor alpha-mediated adiposity-lowering and hypocholesterolemic actions of the selective estrogen receptor modulator acolbifene. Int J Obes (Lond). 2005 Oct;29(10):1236-44. doi: 10.1038/sj.ijo.0803014. PMID: 15925950.
In vitro protocol: 1. Simoncini T, Varone G, Fornari L, Mannella P, Luisi M, Labrie F, Genazzani AR. Genomic and nongenomic mechanisms of nitric oxide synthesis induction in human endothelial cells by a fourth-generation selective estrogen receptor modulator. Endocrinology. 2002 Jun;143(6):2052-61. doi: 10.1210/endo.143.6.8749. PMID: 12021169.
In vivo protocol: 1. Lemieux C, Phaneuf D, Labrie F, Giguère V, Richard D, Deshaies Y. Estrogen receptor alpha-mediated adiposity-lowering and hypocholesterolemic actions of the selective estrogen receptor modulator acolbifene. Int J Obes (Lond). 2005 Oct;29(10):1236-44. doi: 10.1038/sj.ijo.0803014. PMID: 15925950.

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1: Liby K, Rendi M, Suh N, Royce DB, Risingsong R, Williams CR, Lamph W, Labrie F, Krajewski S, Xu X, Kim H, Brown P, Sporn MB. The combination of the rexinoid, LG100268, and a selective estrogen receptor modulator, either arzoxifene or acolbifene, synergizes in the prevention and treatment of mammary tumors in an estrogen receptor-negative model of breast cancer. Clin Cancer Res. 2006 Oct 1;12(19):5902-9. PubMed PMID: 17020999.

2: Al-Dhaheri MH, Shah YM, Basrur V, Pind S, Rowan BG. Identification of novel proteins induced by estradiol, 4-hydroxytamoxifen and acolbifene in T47D breast cancer cells. Steroids. 2006 Nov;71(11-12):966-78. Epub 2006 Sep 1. PubMed PMID: 16949628.

3: Lemieux C, Gélinas Y, Lalonde J, Labrie F, Richard D, Deshaies Y. Hypocholesterolemic action of the selective estrogen receptor modulator acolbifene in intact and ovariectomized rats with diet-induced hypercholesterolemia. Metabolism. 2006 May;55(5):605-13. PubMed PMID: 16631436.

4: Lemieux C, Gélinas Y, Lalonde J, Labrie F, Richard D, Deshaies Y. The selective estrogen receptor modulator acolbifene reduces cholesterolemia independently of its anorectic action in control and cholesterol-fed rats. J Nutr. 2005 Sep;135(9):2225-9. PubMed PMID: 16140902.

5: Berger L, El-Alfy M, Martel C, Labrie F. Effects of dehydroepiandrosterone, Premarin and Acolbifene on histomorphology and sex steroid receptors in the rat vagina. J Steroid Biochem Mol Biol. 2005 Jul;96(2):201-15. PubMed PMID: 15979306.

6: Gauthier S, Cloutier J, Dory YL, Favre A, Mailhot J, Ouellet C, Schwerdtfeger A, Mérand Y, Martel C, Simard J, Labrie F. Synthesis and structure-activity relationships of analogs of EM-652 (acolbifene), a pure selective estrogen receptor modulator. Study of nitrogen substitution. J Enzyme Inhib Med Chem. 2005 Apr;20(2):165-77. PubMed PMID: 15968821.

7: Lemieux C, Phaneuf D, Labrie F, Giguère V, Richard D, Deshaies Y. Estrogen receptor alpha-mediated adiposity-lowering and hypocholesterolemic actions of the selective estrogen receptor modulator acolbifene. Int J Obes (Lond). 2005 Oct;29(10):1236-44. PubMed PMID: 15925950.

8: Lemieux C, Gélinas Y, Lalonde J, Labrie F, Cianflone K, Deshaies Y. Hypolipidemic action of the SERM acolbifene is associated with decreased liver MTP and increased SR-BI and LDL receptors. J Lipid Res. 2005 Jun;46(6):1285-94. Epub 2005 Mar 1. PubMed PMID: 15741653.

9: Liu J, Liu H, van Breemen RB, Thatcher GR, Bolton JL. Bioactivation of the selective estrogen receptor modulator acolbifene to quinone methides. Chem Res Toxicol. 2005 Feb;18(2):174-82. PubMed PMID: 15720121.

10: Labrie F, Champagne P, Labrie C, Roy J, Laverdière J, Provencher L, Potvin M, Drolet Y, Pollak M, Panasci L, L'Espérance B, Dufresne J, Latreille J, Robert J, Samson B, Jolivet J, Yelle L, Cusan L, Diamond P, Candas B. Activity and safety of the antiestrogen EM-800, the orally active precursor of acolbifene, in tamoxifen-resistant breast cancer. J Clin Oncol. 2004 Mar 1;22(5):864-71. PubMed PMID: 14990642.



Additional Information

Acolbifene, formerly known as EM-652, and SCH 57068, is a third generation SERM acting as pure antiestrogen. Acolbifene is also the orally active antiestrogen which is the most potent of the known antiestrogens and exerts pure antiestrogenic activity in the mammary gland and endometrium.
 
Acolbifene is currently in Phase II trials for the prevention of breast cancer sponsored by EndoCeutics, Quebec City, Canada.
 
EM-652 inhibits the AF-1 and AF-2 functions of both ERalpha and beta while the inhibitory action of OH-TAM is limited to AF-2. EM-652 , thus, inhibits Ras-induced transcriptional activity and blocks SRC-1-stimulated activity of the two receptors. The absence of blockade of AF-1 by OH-TAM could explain why resistance develops to Tamoxifen treatment. Not only the development, but also the growth of established DMBA-induced mammary carcinoma is inhibited by treatment with EM-800, the prodrug of EM-652 . EM-652 is the most potent antiestrogen to inhibit the growth of human breast cancer ZR-75-1, MCF-7 and T-47D cells in vitro. When incubated with human Ishikawa endometrial carcinoma cells, EM-800 has no stimulatory effect on the estrogen-sensitive parameter alkaline phosphatase activity. When administered to ovariectomized animals, EM-800 prevents bone loss, and lowers serum cholesterol and triglyceride levels. EM-800 has shown benefits in women with breast cancer who had failed Tamoxifen. The above-summarized preclinical and clinical data clearly suggest the interest of studying this compounds in the neoadjuvant and adjuvant settings and, most importantly, for the prevention of breast and uterine cancer. (s ource: Labrie F, Labrie C, Bélanger A, Simard J, Giguère V, Tremblay A, Tremblay G. J Steroid Biochem Mol Biol. 2001 Dec;79(1-5):213-25 .)