AZD9496
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MedKoo CAT#: 206208

CAS#: 1639042-08-2 (free base)

Description: AZD9496 is a potent and orally bioavailable selective estrogen receptor downregulator and antagonist. AZD9496 can induce ERα degradation in breast cancer cell lines at picomolar concentrations. AZD9496 is curently under clinical trials. AZD9496 may be useful for the treatment of ER+ breast cancer.


Chemical Structure

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AZD9496
CAS# 1639042-08-2 (free base)

Theoretical Analysis

MedKoo Cat#: 206208
Name: AZD9496
CAS#: 1639042-08-2 (free base)
Chemical Formula: C25H25F3N2O2
Exact Mass: 442.18681
Molecular Weight: 442.48
Elemental Analysis: C, 67.86; H, 5.70; F, 12.88; N, 6.33; O, 7.23

Price and Availability

Size Price Availability Quantity
5.0mg USD 90.0 Same day
10.0mg USD 150.0 Same Day
25.0mg USD 250.0 Same Day
50.0mg USD 450.0 Same Day
100.0mg USD 850.0 Same Day
200.0mg USD 1450.0 Same Day
500.0mg USD 2450.0 Same Day
1.0g USD 3850.0 Same Day
2.0g USD 6150.0 Same Day
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Related CAS #: 1639042-08-2 (free base)   1639042-28-6 (maleate)    

Synonym: AZD9496; AZD-9496; AZD 9496.

IUPAC/Chemical Name: (E)-3-(3,5-difluoro-4-((1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylic acid

InChi Key: DFBDRVGWBHBJNR-BBNFHIFMSA-N

InChi Code: InChI=1S/C25H25F3N2O2/c1-14-10-17-16-6-4-5-7-20(16)29-23(17)24(30(14)13-25(2,3)28)22-18(26)11-15(12-19(22)27)8-9-21(31)32/h4-9,11-12,14,24,29H,10,13H2,1-3H3,(H,31,32)/b9-8+/t14-,24-/m1/s1

SMILES Code: O=C(O)/C=C/C1=CC(F)=C([C@H]2N(CC(C)(F)C)[C@H](C)CC3=C2NC4=C3C=CC=C4)C(F)=C1

Appearance: 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: AZD9496 is a potent and selective estrogen receptor (ERα) antagonist with an IC50 of 0.28 nM.
In vitro activity: To measure the rate at which AZD9496 downregulated ERα, SILAC experiments were performed in MCF-7 cells using mass spectroscopy analysis to detect ERα protein levels after treatment with compounds. Addition of AZD9496 increased the rate of degradation of the isotope-labeled ERα compared with DMSO control. Levels of newly synthesized ERα peptide were also reduced following AZD9496 and fulvestrant treatment, presumably due to ongoing degradation of newly synthesized ERα protein by compound present, whereas ERα protein levels continued to increase over time in the presence of tamoxifen or DMSO (Fig. 2). The t1/2 of ERα was decreased from 3 hours, in the presence of DMSO, to 0.75 hours with 100 nmol/L AZD9496 and 0.6 hours with 100 nmol/L fulvestrant (Supplementary Fig. S2). Downregulation of ER occurs through the 26S proteosomal pathway as no decrease in ERα protein level in MCF-7 cells was seen in the presence of the proteosome inhibitor MG132 (Supplementary Fig. S3). In addition, ERα downregulation was shown to be reversible in compound wash-out experiments, where ERα levels increased in a time-dependent manner back to basal levels over a 48-hour period following compound removal (Supplementary Fig. S4). Reference: Cancer Res. 2016 Jun 1;76(11):3307-18. http://cancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=27020862
In vivo activity: To test whether AZD9496 could act as a partial agonist in other tissues, agonist effects were measured in vivo in a previously validated immature female rat model designed to detect agonistic properties of test compounds by measuring increases in uterine weight. AZD9496, given once daily orally at 5 and 25 mg/kg produced statistically significant increases in uterine weight compared with the fulvestrant control (P < 0.001) but significantly lower than tamoxifen (P = 0.001; Fig. 3B). Histologic staining of uterine tissue samples also showed that the lengthening of the endometrial cells in the rat uteri appeared to have decreased compared with tamoxifen (Fig. 3C). In further studies, ERα protein levels were reduced (Fig. 3D). Reference: Cancer Res. 2016 Jun 1;76(11):3307-18. http://cancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=27020862

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
DMSO 88.0 198.88
Ethanol 88.0 198.88

Preparing Stock Solutions

The following data is based on the product molecular weight 442.48 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
In vitro protocol: 1. De Savi C, Bradbury RH, Rabow AA, Norman RA, de Almeida C, Andrews DM, Ballard P, Buttar D, Callis RJ, Currie GS, Curwen JO, Davies CD, Donald CS, Feron LJ, Gingell H, Glossop SC, Hayter BR, Hussain S, Karoutchi G, Lamont SG, MacFaul P, Moss TA, Pearson SE, Tonge M, Walker GE, Weir HM, Wilson Z. Optimization of a Novel Binding Motif to (E)-3-(3,5-Difluoro-4-((1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylic Acid (AZD9496), a Potent and Orally Bioavailable Selective Estrogen Receptor Downregulator and Antagonist. J Med Chem. 2015 Oct 22;58(20):8128-40. doi: 10.1021/acs.jmedchem.5b00984. Epub 2015 Oct 7. PMID: 26407012. 2. Weir HM, Bradbury RH, Lawson M, Rabow AA, Buttar D, Callis RJ, Curwen JO, de Almeida C, Ballard P, Hulse M, Donald CS, Feron LJ, Karoutchi G, MacFaul P, Moss T, Norman RA, Pearson SE, Tonge M, Davies G, Walker GE, Wilson Z, Rowlinson R, Powell S, Sadler C, Richmond G, Ladd B, Pazolli E, Mazzola AM, D'Cruz C, De Savi C. AZD9496: An Oral Estrogen Receptor Inhibitor That Blocks the Growth of ER-Positive and ESR1-Mutant Breast Tumors in Preclinical Models. Cancer Res. 2016 Jun 1;76(11):3307-18. doi: 10.1158/0008-5472.CAN-15-2357. Epub 2016 Mar 28. PMID: 27020862.
In vivo protocol: 1. De Savi C, Bradbury RH, Rabow AA, Norman RA, de Almeida C, Andrews DM, Ballard P, Buttar D, Callis RJ, Currie GS, Curwen JO, Davies CD, Donald CS, Feron LJ, Gingell H, Glossop SC, Hayter BR, Hussain S, Karoutchi G, Lamont SG, MacFaul P, Moss TA, Pearson SE, Tonge M, Walker GE, Weir HM, Wilson Z. Optimization of a Novel Binding Motif to (E)-3-(3,5-Difluoro-4-((1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylic Acid (AZD9496), a Potent and Orally Bioavailable Selective Estrogen Receptor Downregulator and Antagonist. J Med Chem. 2015 Oct 22;58(20):8128-40. doi: 10.1021/acs.jmedchem.5b00984. Epub 2015 Oct 7. PMID: 26407012. 2. Weir HM, Bradbury RH, Lawson M, Rabow AA, Buttar D, Callis RJ, Curwen JO, de Almeida C, Ballard P, Hulse M, Donald CS, Feron LJ, Karoutchi G, MacFaul P, Moss T, Norman RA, Pearson SE, Tonge M, Davies G, Walker GE, Wilson Z, Rowlinson R, Powell S, Sadler C, Richmond G, Ladd B, Pazolli E, Mazzola AM, D'Cruz C, De Savi C. AZD9496: An Oral Estrogen Receptor Inhibitor That Blocks the Growth of ER-Positive and ESR1-Mutant Breast Tumors in Preclinical Models. Cancer Res. 2016 Jun 1;76(11):3307-18. doi: 10.1158/0008-5472.CAN-15-2357. Epub 2016 Mar 28. PMID: 27020862.

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Additional Information

 Related CAS#
CAS#1639042-08-2 ( AZD9496 free base)
CAS#1639042-28-6 ( AZD9496 maleate).