Aromatase (IC50 = 11.5 nM)

In a dose- and time-dependent manner, letrozole (0.1–100 nM; 24-96 hours) strongly suppresses the development of MCF-7 epithelial breast cancer cells [2]. The stimulating impact of testosterone on MCF-7 cell growth is considerably inhibited by letrozole (10 nM) [2]. In MCF-7 cells, letrozole (10 nM; 24-48 hours) reduces the amounts of released metalloproteinases (MMP-2 and MMP-9) [2].

Rats treated with letrozole (3–300 μg/kg; once daily oral gavage for six weeks) show anti-tumor effects[3].

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In vivo, in ACTH-treated rats, CGS 20267 does not affect plasma levels of corticosterone or aldosterone at a dose of 4 mg/kg p.o. (1000 times higher than the ED50 for aromatase inhibition in vivo). In adult female rats, a 14-day treatment with 1 mg/kg p.o. daily, completely interrupts ovarian cyclicity and suppresses uterine weight to that seen 14 days after ovariectomy. In adult female rats bearing estrogen-dependent DMBA-induced mammary tumors, 0.1 mg/kg p.o. given daily for 42 days caused almost complete regression of tumors present at the start of treatment. Thus compared to each other, CGS 16949A and CGS 20267 are both highly potent in inhibiting estrogen biosynthesis in vitro and in vivo. The striking difference between them is that unlike CGS 16949A, CGS 20267 does not affect adrenal steroidogenesis in vitro or in vivo, at concentrations and doses several orders of magnitude higher than those required to inhibit estrogen biosynthesis[1].

CGS 20267 is a new non-steroidal compound which potently inhibits aromatase in vitro (IC50 of 11.5 nM) and in vivo (ED50 of 1-3 micrograms/kg p.o.), CGS 20267 maximally inhibits estradiol production in vitro in LH-stimulated hamster ovarian tissue at 0.1 microM with an IC50 of 0.02 microM and does not significantly affect progesterone production up to 350 microM. In ACTH-stimulated rat adrenal tissue in vitro, aldosterone production was inhibited with an IC50 of 210 microM (10,000 times higher than the IC50 for estradiol production); no significant effect on corticosterone production was seen at 350 microM[1].

Cell Viability Assay[2]
Cell Types: MCF-7 Cell
Tested Concentrations: 0.1, 1, 10, 100 nM
Incubation Duration: 24, 48, 96 hrs (hours)
Experimental Results: Inhibition of cell growth in a dose- and time-dependent manner.

Animal/Disease Models: Adult female rats bearing mammary tumors[3]
Doses: 3, 10, 30, 100, 300 μg/kg
Route of Administration: po (oral gavage) one time/day for 6 weeks
Experimental Results: Induced complete regression of mammary tumors, with an ED50 of 10-30 μg/kg/day.

[1]. Bhatnagar AS, et, al. Highly selective inhibition of estrogen biosynthesis by CGS 20267, a new non-steroidal aromatase inhibitor. J Steroid Biochem Mol Biol. 1990 Dec 20;37(6):1021-7.
[2]. Mitropoulou TN, et, al. Letrozole as a potent inhibitor of cell proliferation and expression of metalloproteinases (MMP-2 and MMP-9) by human epithelial breast cancer cells. Int J Cancer. 2003 Mar 20;104(2):155-60.
[3]. Schieweck K, et, al. Anti-tumor and endocrine effects of non-steroidal aromatase inhibitors on estrogen-dependent rat mammary tumors. J Steroid Biochem Mol Biol. 1993 Mar;44(4-6):633-6.

Letrozole is a member of triazoles and a nitrile. It has a role as an antineoplastic agent and an EC 1.14.14.14 (aromatase) inhibitor.
Letrozole, or CGS 20267, is an oral non-steroidal type II aromatase inhibitor first described in the literature in 1990. It is a third generation aromatase inhibitor like [exemestane] and [anastrozole], meaning it does not significantly affect cortisol, aldosterone, and thyroxine. Letrozole was granted FDA approval on 25 July 1997.
Letrozole is an Aromatase Inhibitor. The mechanism of action of letrozole is as an Aromatase Inhibitor.
Letrozole is a nonsteroidal inhibitor of aromatase which effectively blocks estrogen synthesis in postmenopausal women and is used as therapy of estrogen receptor positive breast cancer, usually after resection and after failure of tamoxifen. Letrozole has been associated with a low rate of serum enzyme elevations during therapy and rare instances of clinically apparent liver injury.
Letrozole is a nonsteroidal inhibitor of estrogen synthesis with antineoplastic activity. As a third-generation aromatase inhibitor, letrozole selectively and reversibly inhibits aromatase, which may result in growth inhibition of estrogen-dependent breast cancer cells. Aromatase, a cytochrome P-450 enzyme localized to the endoplasmic reticulum of the cell and found in many tissues including those of the premenopausal ovary, liver, and breast, catalyzes the aromatization of androstenedione and testosterone into estrone and estradiol, the final step in estrogen biosynthesis.

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Letrozole (INN, trade name Femara®) is an oral non-steroidal aromatase inhibitor that has been introduced for the adjuvant treatment of hormonally-responsive breast cancer. Estrogens are produced by the conversion of androgens through the activity of the aromatase enzyme. Letrozole blocks production of estrogens in this way by competitive, reversible binding to the heme of its cytochrome P450 unit. The action is specific, and letrozole does not reduce production of mineralo- or corticosteroids. In contrast, the antiestrogenic action of tamoxifen, the major medical therapy prior to the arrival of aromatase inhibitors, is due to its interfering with the estrogen receptor, rather than inhibiting estrogen production. Letrozole is approved by the United States Food and Drug Administration (FDA) for the treatment of local or metastatic breast cancer that is hormone receptor positive or has an unknown receptor status in postmenopausal women. Side effects include signs and symptoms of hypoestrogenism. There is concern that long term use may lead to osteoporosis, which is why prescriptions of Letrozole are often accompanied by prescriptions of osteoporosis-fighting medication such as Fosamax. Letrozole has shown to reduce estrogen levels by 98 percent while raising testosterone levels. The anti-estrogen action of letrozole is preferred by athletes and bodybuilders for use during a steroid cycle to reduce bloating due to excess water retention and prevent the formation of gynecomastia related breast tissue that is a side effect of some anabolic steroids. Usage above 2.5 mg/day is known to potentially temporarily kill sex drive. Above 5mg/day for extended periods may cause kidney problems. Letrozole has also been shown to delay the fusing of the growth plates in adolescents. This may boost the effectiveness of growth hormone, and thus Letrozole is used to treat adolescents and children with short stature.

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Letrozole is 99.9% orally bioavailable. A 2.5mg oral dose reaches a Cmax of 104nmol/L with a Tmax of 8.10h, and an AUC of 7387nmol\*h/L.
The terminal elimination half life of letrozole is approximately 42h in healthy volunteers, but longer in breast cancer patients.

C17H11N5

285.3

263.14224

C, 71.57; H, 3.89; N, 24.55

112809-51-5

Letrozole-d4;1133712-96-5

3902

Typically exists as white to off-white solids at room temperature

1.1±0.1 g/cm3

472.0±55.0 °C at 760 mmHg

181-183ºC

214.2±24.5 °C

0.0±1.2 mmHg at 25°C

1.615

3.7

78.29

N#CC1=CC=C(C(C2=CC=C(C#N)C=C2)N3N=CN=C3)C=C1

HPJKCIUCZWXJDR-UHFFFAOYSA-N

InChI=1S/C17H11N5/c18-9-13-1-5-15(6-2-13)17(22-12-20-11-21-22)16-7-3-14(10-19)4-8-16/h1-8,11-12,17H

4-[(4-cyanophenyl)-(1,2,4-triazol-1-yl)methyl]benzonitrile

Abbreviation; CGS 20267; CGS20267; CGS-20267; LTZ; Trade name: Femara; Letoval; Femara; 4,4'-((1h-1,2,4-triazol-1-yl)methylene)dibenzonitrile; Letrozol;

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Solubility in Formulation 1: ≥ 2.08 mg/mL (7.29 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.

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Solubility in Formulation 2: ≥ 2.08 mg/mL (7.29 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.

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Solubility in Formulation 3: ≥ 2.08 mg/mL (7.29 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 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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Solubility in Formulation 4: 0.5% CMC: 10 mg/mL

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 (Please use freshly prepared in vivo formulations for optimal results.)