The preclinical pharmacology of “Arimidex” (Anastrozole; ZD1033) — a potent, selective aromatase inhibitor

Anastrozole is a comparatively simple, achiral benzyltriazole derivative, 2,2′-[5-(1H-1,2,4-triazol-1-ylmethyl)-1,3-phenylene]bis(2-methylpropiononitrile), that inhibits human placental aromatase with an IC 50 of 15 nM and elicits maximal activity in vivo in rats (inhibition of ovulation and androst...

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Bibliographic Details
Published in:The Journal of steroid biochemistry and molecular biology 1996-07, Vol.58 (4), p.439-445
Main Authors: Dukes, Michael, Edwards, Philip N., Large, Michael, Smith, Ian K., Boyle, Thomas
Format: Article
Language:English
Subjects:
Adrenal Glands - drug effects
Aminoglutethimide - pharmacology
Anastrozole
Androstenedione - analogs & derivatives
Androstenedione - pharmacology
Animals
Aromatase Inhibitors
Cortodoxone - metabolism
Enzyme Inhibitors - pharmacology
Fadrozole - pharmacology
Female
Hormones - blood
Humans
Macaca nemestrina
Male
Metyrapone - pharmacology
Nitriles - pharmacology
Organ Size
Potassium - urine
Prostate - drug effects
Rats
Rats, Wistar
Seminal Vesicles - drug effects
Sodium - urine
Triazoles - pharmacology
Uterus - drug effects
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Summary:Anastrozole is a comparatively simple, achiral benzyltriazole derivative, 2,2′-[5-(1H-1,2,4-triazol-1-ylmethyl)-1,3-phenylene]bis(2-methylpropiononitrile), that inhibits human placental aromatase with an IC 50 of 15 nM and elicits maximal activity in vivo in rats (inhibition of ovulation and androstenedione-induced uterine hypertrophy) and monkeys (lowering of plasma oestradiol) at 0.1 mg/kg p.o. At 30 times this dose, anastrozole does not elevate plasma 11-deoxycorticosterone in monkeys, and at 100 times this dose, does not affect plasma aldosterone levels or Na + K + excretion in rats, plasma K + concentrations in dogs, or cause adrenal hypertrophy in rats or dogs. It therefore has no discernible effect on adrenocorticoid hormone synthesis in vivo at very large multiples of its maximally effective aromatase-inhibiting dose. At similar large multiples in rats it displays no oestrogenic, anti-oestrogenic, androgenic, anti-androgenic, progestogenic, glucocorticoid, antiglucocorticoid or mineralocorticoid activity. Anastrozole is thus a potent and highly selective aromatase inhibitor, with no intrinsic hormonal activities—a pharmacological profile particularly suitable for the treatment of breast cancer.
ISSN:0960-0760
1879-1220
DOI:10.1016/0960-0760(96)00064-7