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Inhibitors of oestrogen biosynthesis: preclinical studies with CGS 16949A, a new nonsteroidal aromatase inhibitor

Published online by Cambridge University Press:  05 December 2011

Ajay S. Bhatnagar
Research Department, Pharmaceuticals Division, CIBA-GEIGY Limited, 4002 Basel, Switzerland
Klaus Schieweck
Research Department, Pharmaceuticals Division, CIBA-GEIGY Limited, 4002 Basel, Switzerland
Albert Häusler
Research Department, Pharmaceuticals Division, CIBA-GEIGY Limited, 4002 Basel, Switzerland
Leslie J. Browne
Research Department, Pharmaceuticals Division, CIBA-GEIGY Corporation, Summit, NJ 07901, U.S.A.
Ronald E. Steele
Research Department, Pharmaceuticals Division, CIBA-GEIGY Corporation, Summit, NJ 07901, U.S.A.
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Inhibitors of the aromatase enzyme represent a class of therapeutic agents which potently inhibit oestrogen biosynthesis in vivo. This inhibition of oestrogen biosynthesis is well established as effective therapy in the treatment of oestrogen-dependent breast cancer. CGS 16949A [4-(5,6,7,8-tetrahydroimidazo-[l,5-a]pyridin-5-yl)-benzonitrile hydrochloride] is a non-steroidal imidazole derivative which is a potent competitive aromatase inhibitor in vitro. At a maximally effective concentration, it selectively inhibits aromatase and does not affect glucocorticoid production from the adrenal in vitro.

In vivo in the rat, CGS 16949A effectively reduces ovarian oestrogen content and potently inhibits an aromatase-mediated androgen-induced uterine hypertrophy. Oral treatment of adult, cyclic female rats with CGS 16949A disrupts cyclicity, inhibits ovulation, reduces uterine weight and suppresses serum oestradiol, all expected sequelae of oestrogen deprivation. At maximally effective doses, there is no evidence of adrenal hypertrophy, indicating that adrenal steroidogenesis is unaffected. In the DMBA-induced mammary carcinoma model in the rat, CGS 16949A caused almost complete regression of palpable tumours and significantly suppressed the appearance of new tumours at a maximally effective oral dose. Thus, CGS 16949A is a potent and selective inhibitor of the aromatase enzyme. In the rat, it is very efficacious in inhibiting oestrogen biosynthesis and in suppressing the growth of DMBA-induced mammary tumours.

Research Article
Copyright © Royal Society of Edinburgh 1989

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