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

• 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
• ISSN: 0960-0760; 1879-1220
• DOI: 10.1016/0960-0760(96)00064-7

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.