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Aromatase inhibitors — mechanisms for non-steroidal inhibitors


The conversion of androgens to estrogens occurs in a variety of cells and tissues, such as ovarian granulosa and testicular cells, placenta, adipose tissue, and various sites of the brain. The extragonadal synthesis of estrogens has great pathophysiological importance. Estrogens produced by, for example, adipose tissue have a role in the pathogenesis of certain forms of breast cancer and endometrial adenocarcinoma. The biosynthesis of estrogens is catalyzed by the aromatase, an enzyme localized in the endoplasmic reticulum that consists of two components: a cytochrome P450 (P450 Arom, P450 19 product of theCYP 19 gene) and the NADPH cytochrome P450 reductase. The alignment of the amino acid sequences of human P450 19 with other mammalian P450s shows little sequence similarity, which indicates not only that P450 19 is a unique form of the P450 superfamily but also that the aromatase may be a good target for the development of selective P450 inhibitors.

Aminoglutethimide (AG) is the pioneer drug of the reversible competitive nonsteroidal aromatase inhibitors. Since AG is a nonspecific aromatase inhibitor and presents some problems with tolerability, a number of structural analogues have been synthesized. For example, rogletimide is slightly less potent than AG but has the advantage of not inhibiting the cholesterol side-chain cleavage and is devoid of sedative action. Elongation of the ethyl substituent of AG and rogletimide leads to an increase in aromatase inhibition. Further studies led to the discovery of a new generation of much more potent aromatase inhibitors. An example is fadrozole. However, although fadrozole is a poor inhibitor of the cholesterol side-chain cleavage, it suppresses aldosterone release by ACTH-stimulated human adrenocortical cells. More selective aromatase inhibitors are the triazole derivatives. Examples are CGS 20267, CGS 47645, R 76 713, and ICI D1033.

R 76 713's aromatase inhibitory effect is largely due to its (+)-S-enantiomer, vorozole. Computer modeling studies of the interaction of vorozole with part of the “I-helix” of P450 19 suggest that the chlorine-substituted phenyl ring of vorozole interacts with the gamma-carbonyl group of Glu-302. Thr-310, which corresponds to the highly conserved Thr-252 in P450 101, interacts with vorozole's triazole ring, and the 1-methyl-benzotriazole moiety binds near Asp-309.

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Correspondence to Hugo Vanden Bossche.

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Bossche, H.V., Moereels, H. & Koymans, L.M.H. Aromatase inhibitors — mechanisms for non-steroidal inhibitors. Breast Cancer Res Tr 30, 43–55 (1994).

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Key words

  • P450 19
  • aromatase inhibitors
  • endocrine therapy
  • aminoglutethimide
  • rogletimide
  • fadrozole
  • vorozole
  • CGS 20267
  • CGS 47465