Description
Letrozole, also known as Femara or 112809-51-5, is an orally active aromatase inhibitor that works by competitively inhibiting aromatase. This inhibition prevents the conversion of androgens to estrogen (estrogen stimulates breast tissues and breast cancer reoccurrence) and gonadal steroidogenesis. It can be used for the treatment of breast cancer that is hormonally-responsive or has an unknown receptor status in postmenopausal women. Besides this, Letrozole also has some off-label use such as ovarian stimulation, pretreatment of termination of pregnancy, treatment of gynecomastia, treatment of endometriosis, and promoting spermatogenesis for male patients of nonobstructive azoospermia.
Chemical Properties
white to light yellow crystal
Originator
Novartis (Switzerland)
Uses
A nonsteroidal aromatase inhibitor structurally related to Fadrozole. Antineoplastic
Definition
ChEBI: 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.
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)
Brand name
Femara (Novar tis).
Therapeutic Function
Antineoplastic
General Description
Letrozole, 4,4'-(1H-1,2,4-triazol-1-ylmethylene)dibenzonitrile (Femara), is used for most of thesame indications as anastrozole. It reduces concentrations ofestrogens by 75% to 95%, with maximal suppressionachieved within 2 to 3 days. Letrozole is specific for aromataseinhibition, with no additional effects on adrenal corticoidbiosynthesis. CYPs 3A4 and 2A6 are involved in themetabolism of letrozole to the major carbinol metabolite,which is inactive. The loss of the triazole ring, which is involvedin coordination of the heme iron, would explain theloss of activity. Letrozole strongly inhibits CYP2A6 invitro, with moderate inhibition of CYP2C19. The effect ofthis in vitro inhibition on the pharmacokinetics of coadministereddrugs is unknown. Tamoxifen reduces the levels ofletrozole significantly if they are used together, so combinationtreatment with these agents is not recommended.
Biological Activity
Letrozole is a potent, cell-permeable inhibitor of aromatase (IC50 = 2 nM). It inhibits proliferation of estrogen receptor-positive (ER+) MCF-7 cells when used alone at concentrations ranging from 0.1 to 100 nM and when used at a concentration of 10 nM in combination with testosterone or 4-androstene-3,17-dione. It also reduces matrix metalloproteinase-2 (MMP-2) and MMP-9 levels in MCF-7 cells when used at a concentration of 10 nM. Letrozole (10 μg per day) reduces tumor growth in an MCF-7Ca ovariectomized-mouse xenograft model. Formulations containing letrozole have been used in the treatment of postmenopausal breast cancer.
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
