Anastrozole (Arimidex)

[MaNiCC]

nastrozole (INN, trade name Arimidex, AstraZeneca) is a drug used to treat breast cancer after surgery and for metastases in post-menopausal women. Anastrozole is an aromatase inhibitor, which means that it interrupts a critical step in the body’s synthesis of estrogen. Some breast cancer cells require estrogen to grow, and eliminating estrogen suppresses their growth.
Annual sales approx $2.2bn. Patent expires 2010 in the US[1]; however, the generic form is available in some other markets.





Systematic (IUPAC) name
Identifiers
CAS number 120511-73-1
ATC code L02BG03
PubChem CID 2187
DrugBank APRD00016
ChemSpider 2102

Chemical data
Formula C17H19N5
Mol. mass 293.366 g/mol
SMILES eMolecules & PubChem

Pharmacokinetic data
Bioavailability 83-85%
Protein binding 40%
Metabolism 85% hepatic
Half-life 72 h
Excretion 11% renal

Therapeutic considerations
Pregnancy cat. ?
Legal status Rx only (U.S.)
Routes oral
Clinical trials

The ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial was an international randomised controlled trial of 9366 women with localized breast cancer who received either anastrozole, tamoxifen, or both for five years, followed by five years of follow-up.[2] After more than 5 years the group that received anastrozole had significantly better clinical results than the tamoxifen group. The trial suggested that anastrozole is the preferred medical therapy for postmenopausal women with localized breast cancer that is estrogen receptor (ER) positive.
Another study found that the risk of recurrence was reduced 40% (with some risk of bone fracture) and that ER negative patients also benefited from switching to Arimidex.


Mechanism of Action
Anastrozole inhibits the enzyme aromatase, which is responsible for converting androgens to estrogens. Anastrozole binds reversibly to the aromatase enzyme through competitive inhibition.
Elevated levels of estrogens may increase the severity of breast cancer, as sex hormones can cause hyperplasia and differentiation at estrogen receptor sites.


Side effects
Bone weakness : Women who switched to Arimidex (after two years on tamoxifen) reported twice as many fractures as those who continued to take tamoxifen (2.1% compared to 1%).
Bisphosphonates are sometimes prescribed to prevent the osteoporosis induced by aromatase inhibitors but have another serious side effect, osteonecrosis of the jaws. Since statins have a bone strengthening effect , combining a statin with an aromatase inhibitor may avoid both fractures and possible cardiovascular risks without jaw osteonecrosis. In one study of women with breast cancer taking anastrozole, statin use was associated with a 38% reduced fracture risk, or approximately the equivalent of 10 mg Fosamax daily.


Usage for men
While officially indicated for women, this drug has proven effective in the off-label use of reducing estrogens (in particular and more importantly, estradiol) in men. Excess estradiol in men can cause benign prostatic hyperplasia, gynecomastia, and symptoms of hypogonadism. Some athletes and body builders will also use anastrozole as a part of their steroid cycle to reduce and prevent symptoms of excess estrogens; in particular, gynecomastia and water retention.
Study data currently suggest that dosages of 0.5 mg to 1 mg a day reduce serum estradiol by about 50% in men, which differs from the typical reduction in postmenopausal women. However the reduction may be different for men with grossly elevated estradiol (clinical data are currently lacking).


Usage for children
This drug is frequently used in the treatment of children with growth disorder to stop or slow the onset of puberty. The cause of the growth disorder is through hormones which may trigger the early onset of puberty. At the onset of puberty the bone growth plates begin to close. This can occur in children as young as 5 years old, so for children severely behind in growth, the opportunity for increased growth is diminished. Arimidex is shown to slow or stop this process.


Chemistry
The synthesis begins with nucleophilic substitution of two benzylic bromides in α,α’-dibromomesitylene (prepared by radical bromination of mesitylene, not shown on the scheme) with cyanide by treatment with potassium cyanide under phase transfer conditions, affording the dinitrile. Exhaustive methylation with methyl iodide and sodium hydride leads to the replacement of the more acidic side chain hydrogen atoms by methyl groups. Treatment with bromine in the presence of benzoyl peroxide leads to the formation of the corresponding benzyl bromide. Reaction of that product with 1,2,4-triazole in the presence of a base completes the synthesis of the aromatase inhibitor.