112809-51-5 Usage
Description
Letrozole, also known as 4,4'-(1H-1,2,4-triazol-1-ylmethylene)dibenzonitrile (Femara), is an orally active nonsteroidal aromatase inhibitor. It is a potent, cell-permeable inhibitor of aromatase with an IC50 of 2 nM. Letrozole is specific for aromatase inhibition, with no additional effects on adrenal corticoid biosynthesis. It reduces concentrations of estrogens by 75% to 95%, with maximal suppression achieved within 2 to 3 days. As a competitive inhibitor of the aromatase, Letrozole inhibits the conversion of androgens to estrogen, which stimulates breast tissues and breast cancer reoccurrence, and gonadal steroidogenesis. It is used for the treatment of breast cancer that is hormonally-responsive or has an unknown receptor status in postmenopausal women. Letrozole is also used for off-label purposes such as ovarian stimulation, pretreatment of termination of pregnancy, treatment of gynecomastia, treatment of endometriosis, and promoting spermatogenesis for male patients of nonobstructive azoospermia. It is a white to light yellow crystal and is marketed under the brand name Femara (Novartis).
Uses
Used in Organoid Growth Assay:
Letrozole is used as an inhibitor to determine its inhibitory capacity in organoid growth assays.
Used in Steroid Receptor Coactivator-1 (SRC-1) Mediated Endogenous Estrogen Regulation of Hippocampal PSD-95:
Letrozole is used to investigate the role of SRC-1 in endogenous estrogen regulation of hippocampal PSD-95.
Used in Determining Effects on Tumor-Induced Hyperalgesia:
Letrozole is used to determine its effects on tumor-induced hyperalgesia.
Used in Hormonal Manipulation in Rats:
Letrozole is used for hormonal manipulation in rats.
Used in Studying Effects on Lipocalin-2 (Lcn2):
Letrozole is used to study its effects on lipocalin-2 (Lcn2).
Used in Determining Effects on Mechanical Hyperalgesia and Aromatase Expression:
Letrozole is used to determine its effects on mechanical hyperalgesia and aromatase expression.
Used in Antineoplastic Applications:
As a nonsteroidal aromatase inhibitor structurally related to Fadrozole, Letrozole is used for antineoplastic purposes, reducing estrogen levels to inhibit the growth of estrogen receptor-positive tumors.
Used in Postmenopausal Breast Cancer Treatment:
Formulations containing Letrozole have been used in the treatment of postmenopausal breast cancer, where it reduces tumor growth in an MCF-7Ca ovariectomized-mouse xenograft model.
Indications and uses
Letrozole is part of a new generation of highly selective aromatase inhibitors and is an artificially synthesized benzotriazole derivative. Letrozole inhibits aromatase to lower estrogen levels, thus preventing estrogen from stimulating tumor growth. Its in vivo activity is 150-250 times stronger than that of first generation aromatase inhibitor Amarante. As it is highly selective, it will not impact glucocorticoid, mineralocorticoid and thyroid functions; even at high dosages, it will not have any inhibiting effects on adrenal corticosteroid secretion, giving it a high treatment index. Letrozole has no latent toxicity towards any bodily systems and target organs, has no mutagenicity and carcinogenic effects, has minimal toxic side effects, is well-tolerated, and has stronger anticancer effects than other aromatase inhibitors and antiestrogen drugs. Letrozole is suitable for advanced breast cancer postmenopausal patients who have not responded to estrogen-suppressing treatment and for early breast cancer treatment. It is used to treat postmenopausal patients with advanced breast cancer and serves as a second-line treatment to follow unsuccessful antiestrogen treatment. Compared to the current standard Tamoxifen treatment, Letrozole can better prevent the risk of breast cancer recurrence.
Pharmacokinetics
Absorption of oral letrozole is rapid and complete and steady state is achieved in 2–6 weeks with administration of letrozole 2.5mg once daily. The major route of elimination of letrozole is via metabolism to a pharmacologically inactive carbinol metabolite. The cytochrome P450 (CYP) 3A4 and CYP2A6 isozymes metabolize letrozole to a pharmacologically inactive carbinol metabolite. Renal excretion of a glucuronide conjugate of the carbinol metabolite of letrozole represents the major route of drug clearance.
Side effects
Randomized grouping studies have shown that daily oral ingestion of 2.5mg Letrozole leads to a 33% rate of drug-related negative reactions, a percentage much lower than AG group’s 46%. Negative reactions to Letrozole are mostly mild or moderate, consisting mostly of nausea (2-9%), headache (0-7%), bone pain (4-10%), hot flashes (0-9%) and weight gain (2-8%). Other uncommon side effects include constipation, diarrhea, itching, rash, joint pain, chest pain, abdominal pain, fatigue, insomnia, dizziness, edema, high blood pressure, arrhythmia, thrombosis, dyspnea, vaginal bleeding, etc.
Originator
Novartis (Switzerland)
Manufacturing Process
From 4-bromomethylbenzonitrile and 1H-[1,2,4]triazole was obtained 4-
[1,2,4]triazol-1-ylmethylbenzonitrile. Treatment of that with strong base (tertBuOK) results in formation of the anion by removal of the relatively acidic
benzyl proton. This anion was condensed with p-fluorobenzinitrile to give
benzhydryl tetrazole (Letrozole)
Therapeutic Function
Antineoplastic
Biochem/physiol Actions
Letrozole is a third generation nonsteroidal aromatase inhibitor. It is a competitive inhibitor of the aromatase enzyme system and thus inhibits the conversion of androgens to estrogens. Letrozole inhibits the aromatase enzyme by competitively binding to the heme of the cytochrome P450 subunit of the enzyme, resulting in a reduction of estrogen biosynthesis in all tissues.
Mechanism of action
Inhibition of arom atase by letrazole is competitive and highly specific , with no effect on enzymes that are responsible for the production of glucocorticosteroids and mineralocorticosteroids. This agent is significantly more effective than tamoxifen in treating horm one-dependent cancer.
Clinical Use
Femara was launched in France and the UK for second-line treatment of
advanced breast cancer. Letrazole can be synthesized in two steps from 4-
bromomethyl-benzonitrile with 1,2,4-triazole and is a third generation aromatase
inhibitor. It is a highly specific inhibitor of P450arom which prevents the conversion of
androstenedione to estrone. The reduction of plasma estrogen was immediate and
long lasting. This is accomplished with no inhibition of other steroid biosynthesis
making it the most selective aromatase inhibitor tested. Letrazole has remarkable
antitumor activity, is well tolerated and has no toxic side effects. It is 10,000 times
more potent than aminoglutethimide, in vivo, the first well established aromatase
inhibitor.
Drug interactions
Potentially hazardous interactions with other drugs
None known
Metabolism
Metabolic clearance via the cytochrome P450 isoenzymes
3A4 and 2A6 to a pharmacologically inactive carbinol
metabolite is the major elimination pathway of letrozole.
Formation of minor unidentified metabolites and direct
renal and faecal excretion play only a minor role in the
overall elimination of letrozole. Within 2 weeks after
administration of 2.5 mg [14C]-labelled letrozole to
healthy postmenopausal volunteers, 88.2 ± 7.6% of the
radioactivity was recovered in urine and 3.8 ± 0.9% in
faeces. At least 75% of the radioactivity recovered in urine
up to 216 hours (84.7 ± 7.8% of the dose) was attributed
to the glucuronide of the carbinol metabolite, about 9%
to two unidentified metabolites, and 6% to unchanged
letrozole
References
https://www.drugbank.ca/drugs/DB01006
https://en.wikipedia.org/wiki/Letrozole
Check Digit Verification of cas no
The CAS Registry Mumber 112809-51-5 includes 9 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 6 digits, 1,1,2,8,0 and 9 respectively; the second part has 2 digits, 5 and 1 respectively.
Calculate Digit Verification of CAS Registry Number 112809-51:
(8*1)+(7*1)+(6*2)+(5*8)+(4*0)+(3*9)+(2*5)+(1*1)=105
105 % 10 = 5
So 112809-51-5 is a valid CAS Registry Number.
InChI:InChI=1/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
112809-51-5Relevant articles and documents
A novel process for the synthesis of substantially pure Letrozole
Suman,Vijayabhaskar,NageswaraRao,Syam Kumar,VenkateswaraRao
, p. 1 - 8 (2019)
This article demonstrates an improved novel and practical synthesis of oral non-steroidal aromatase inhibitor (AI) Letrozole in a five-stage synthetic process in excellent yields. Key steps of the synthesis involve the condensation of 4-(chloro(4-cyanophenyl)methyl)benzamide with 1H-1,2,4-triazole and further its dehydration to Letrozole by using trifluoroacetic anhydride at low temperature.
Nickel-Catalyzed Cyanation of Aryl Thioethers
Delcaillau, Tristan,Woenckhaus-Alvarez, Adrian,Morandi, Bill
supporting information, p. 7018 - 7022 (2021/09/13)
A nickel-catalyzed cyanation of aryl thioethers using Zn(CN)2 as a cyanide source has been developed to access functionalized aryl nitriles. The ligand dcype (1,2-bis(dicyclohexylphosphino)ethane) in combination with the base KOAc (potassium acetate) is essential for achieving this transformation efficiently. This reaction involves both a C-S bond activation and a C-C bond formation. The scalability, low catalyst and reagents loadings, and high functional group tolerance have enabled both late-stage derivatization and polymer recycling, demonstrating the reaction's utility across organic chemistry.
Immobilized palladium nanoparticles on a cyclodextrin-polyurethane nanosponge (Pd-CD-PU-NS): An efficient catalyst for cyanation reaction in aqueous media
Khajeh Dangolani, Soheila,Sharifat, Sara,Panahi, Farhad,Khalafi-Nezhad, Ali
supporting information, p. 256 - 265 (2019/06/07)
Immobilized palladium nanoparticles on a cyclodextrin-polyurethane nanosponge (Pd-CD-PU-NS) were found to be an efficient heterogeneous catalyst in the cyanation reaction of aryl halides in aqueous media. This catalyst system is containing palladium nanoparticles with a size of ～7 nm. Moreover, the CD-PU-NS support formed microsphere-shaped structures with a size of ～100–200 nm. The TEM images show that Pd nanoparticles were formed in near spherical shape morphology and were immobilized in the structure of the CD-PU-NS support. Under our optimized reaction conditions, aryl cyanides were obtained in high yields in the presence of the Pd-CD-PU-NS catalyst. Our results demonstrated that the Pd-CD-PU-NS catalyst is highly effective in the cyanation reaction in aqueous media. Furthermore, the catalyst could be simply extracted from the reaction mixture, providing an efficient methodology for the synthesis of aryl cyanides. The Pd-CD-PU-NS catalyst could be recycled four times with almost consistent catalytic efficiency.
