Skip to main content
SpringerLink
Log in

Aromatase inhibitors — mechanisms for non-steroidal inhibitors

  • Published:
Breast Cancer Research and Treatment Aims and scope Submit manuscript

Summary

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Simpson ER, Kilgore MW, Mahendroo MS, Means GD, Corbin CJ, Mendelson CR: Regulation of human aromatase cytochrome P450 gene expression. J Steroid Biochem Mol Biol 43:923–930, 1992

    Google Scholar 

  2. Cole PA, Robinson CH: A peroxide model for placental aromatase. J Am Chem Soc 110:1284–1285, 1988

    Google Scholar 

  3. Graham-Lorence S, Khalil MW, Lorence MC, Mendelson CR, Simpson ER: Structure-function relationships of human aromatase cytochrome P-450 using molecular modeling and site-directed mutagenesis. J Biol Chem 266:11939–11946, 1991

    Google Scholar 

  4. McPhaul MJ, Noble JF, Simpson ER, Mendelson CR, Wilson JD: The expression of a functional cDNA encoding the chicken cytochrome P450 Arom (aromatase) that catalyses the formation of estrogen from androgen. J Biol Chem 263:16358–16363, 1988

    Google Scholar 

  5. Corbin CJ, Graham-Lorence S, McPhaul MJ, Mason JI, Mendelson CR, Simpson ER: Isolation of a full-length cDNA insert encoding human aromatase system cytochrome P450 and its expression in nonsteroidogenic cells. Proc Natl Acad Sci USA 85:8948–8952, 1988

    Google Scholar 

  6. Pompon D, Liu RY-K, Besman MJ, Wang PL, Shively JE, Chen S: Expression of human placental aromatase inSaccharomyces cerevisiae. Mol Endocrinol 3:1477–1487, 1989

    Google Scholar 

  7. McNatty KP, Baird DT, Boltan A, Chambers P, Corker CS, McLean H: Concentration of oestrogens and androgens in human ovarian follicular fluid throughout the menstrual cycle. J Endocrinol 71:77–85, 1976

    Google Scholar 

  8. Sasano H, Okamoto M, Mason JI, Simpson ER, Mendelson CR, Sasano N, Silverberg SC: Immunolocalization of aromatase, 17α-hydroxylase and side-chain cleavage cytochromes P450 in human ovary. J Reprod Fertil 85:163–169, 1989

    Google Scholar 

  9. Santen RJ: Potential clinical use of new aromatase inhibitors. Steroids 50:575–593, 1987

    Google Scholar 

  10. Edman CD, MacDonald PC: Effect of obesity on conversion of plasma androstenedione to estrone in ovulatory and anovulatory young women. Am J Obstet Gynecol 130:456–461, 1978

    Google Scholar 

  11. Killinger DW, Perel E, Daniilescu D, Kharlip L, Martin E: Aromatase activity in the breast and other peripheral tissues and its therapeutic regulation. Steroids 50: 523–536, 1987

    Google Scholar 

  12. Miller WR, O'Neil J: The importance of local synthesis of estrogen within the breast. Steroids 50: 537–548, 1987

    Google Scholar 

  13. James VHT, Reed MJ, Lai LC, Ghilchik MW, Tait GH, Newton CJ, Coldham NG: Regulation of estrogen concentrations in human breast tissues. Ann NY Acad Sci 595:227–235, 1990

    Google Scholar 

  14. Vermeulen A, Deslypere JP, Paridaens R, Leclercq G, Roy F, Heuson JC: Aromatase, 17ß-hydroxysteroid dehydrogenase and intratissular sex hormone concentrations in cancerous and normal glandular breast tissue in postmenopausal women. Eur J Cancer Clin Oncol 22:515–525, 1986

    Google Scholar 

  15. Miller WR, O'Neil J: The significance of steroid metabolism in human cancer. J Steroid Biochem Mol Biol 37:317–325, 1990

    Google Scholar 

  16. Thijssen JHH, Blankenstein MA, Donker GH, Daroszewski: Endogenous steroid hormones and local aromatase activity in the breast. J Steroid Biochem Mol Biol 39:799–804, 1991

    Google Scholar 

  17. Reed MJ, Singh A, Ghilchik MW, Coldham NG, Purohit A: Regulation of oestradiol 17ß-hydroxysteroid dehydrogenase in breast tissues: the role of growth factors. J Steroid Biochem Mol Biol 39:791–798, 1991

    Google Scholar 

  18. Jackson IM, Lowery C: Clinical uses of antiestrogens.In: Furr BJA, Wakeling AE (eds) Pharmacology and Clinical Uses of Inhibitors of Hormone Secretion and Action. Ballière Tindall, London, 1987, p 87–105

    Google Scholar 

  19. Manni A, Santen RJ: Clinical uses of aromatase inhibitors.In: Furr BJA, Wakeling AE (eds) Pharmacology and Clinical Uses of Inhibitors of Hormone Secretion and Action. Ballière Tindall, London, 1987, p 271–287

    Google Scholar 

  20. Banting L, Nichols PJ, Shaw MA, Smith HJ: Recent developments in aromatase inhibition as a potential treatment for oestrogen-dependent breast cancer.In: Ellis GP, West GB (eds) Progress in Medicinal Chemistry. Elsevier Science Publishers, Amsterdam, 1989, vol 26, p 253–298

    Google Scholar 

  21. Miller WR: Endocrine treatment for breast cancers: biological rationale and current progress. J Steroid Biochem Mol Biol 37:467–480, 1990

    Google Scholar 

  22. Nicholson RI, Walker KJ, Bouzubar N, Wills RJ, Gee JMW, Rushmere NK, Davies P: Estrogen deprivation in breast cancer. Ann NY Acad Sci 595:316–327, 1990

    Google Scholar 

  23. Dickson RB, Thompson EW, Lippman ME: Regulation of proliferation, invasion and growth factor synthesis in breast cancer by steroids. J Steroid Biochem Mol Biol 37:305–316, 1990

    Google Scholar 

  24. Brodie A: Aromatase and its inhibitors — an overview. J Steroid Biochem Mol Biol 40:255–261, 1991

    Google Scholar 

  25. Dowsett M: Inhibitors of steroidogenic enzymes for the treatment of breast cancer. J Steroid Biochem Mol Biol 39:805–809, 1991

    Google Scholar 

  26. Pérez N, Borja J: Aromatase inhibitors: clinical pharmacology and therapeutic implications in breast cancers. J Intern Med Res 20:303–312, 1992

    Google Scholar 

  27. Pasqualini JR, Giambiagi N, Gelly C, Chetrite G: Antiestrogen action in mammary cancer and in fetal cells. J Steroid Biochem Mol Biol 37:343–348, 1990

    Google Scholar 

  28. Nadjafi C: Aminoglutethimide chemistry, pharmacokinetics, pharmacology and mechanism of action. Acta Clin Belg 41 (suppl II): 3–11, 1986

    Google Scholar 

  29. Uzgiris VI, Whipple CA, Salhanick HA: Stereoselective inhibition of cholesterol side chain cleavage by enantiomers of aminoglutethimide. Endocrinology 101: 89–92, 1977

    Google Scholar 

  30. Walther B, Ghersi-Egea JF, Minn A, Siest G: Brain mitochondrial cytochrome P450scc: spectral and catalytic properties. Arch Biochem Biophys 254:592–596, 1987

    Google Scholar 

  31. Georgiou M, Perkins LM, Payne AH: Steroid synthesis-dependent oxygen-mediated damage of mitochondrial and microsomal cytochrome P450 enzymes in rat Leydig cell cultures. Endocrinology 121:1390–1399, 1987

    Google Scholar 

  32. Santen RJ, Cohn N, Misbin R, Samojlik E, Foltz E: Acute effects of aminoglutethimide on testicular steroidogenesis in normal men. J Clin Endocrinol Metab 49:631–634, 1979

    Google Scholar 

  33. Santen RJ, Misbin RI: Aminoglutethimide: review of pharmacology and clinical uses. Pharmacotherapy 1:95–120, 1981

    Google Scholar 

  34. Touitou Y, Bogdan A, Legrand JC, Desgrez P: Aminoglutethimide and glutethimide: effects on 18-hydroxycorticosterone biosynthesis by human and sheep adrenalsin vitro. Acta Endocrinol 80:517–526, 1975

    Google Scholar 

  35. Dexter RN, Fishman LM, Ney RL, Liddle GW: Inhibition of adrenal corticosteroid synthesis by aminoglutethimide: studies of the mechanisms of action. J Clin Endocrinol Metab 27:473–480, 1967

    Google Scholar 

  36. Thompson EA, Siiteri PK: The involvement of human placental microsomal cytochrome P450 in aromatization. J Biol Chem 249:5373–5378, 1974

    Google Scholar 

  37. Salhanick HA: Basic studies on aminoglutethimide. Cancer Res 42 (Suppl 2):3315S-3321S, 1982

    Google Scholar 

  38. Foster AB, Jarman M, Leung C-S, Rowlands MG, Taylor GN, Plevey RG, Sampson P: Analogues of aminoglutethimide: selective inhibition of aromatase. J Med Chem 28:200–204, 1985

    Google Scholar 

  39. Leung CS, Rowlands MG, Jorman M, Foster AB, Griggs LS, Wilman DEV: Analogues of 3-ethyl-3-(4-pyridyl)piperidine-2,6-diones as selective inhibitors of aromatase derivatives with variable 1-alkyl and 3-alkyl substituents. J Med Chem 30:1550–1554, 1987

    Google Scholar 

  40. Santen RJ, Manni A, Harvey H, Redmond C: Endocrine treatment of breast cancer in women. Endocr Rev 11:221–265, 1990

    Google Scholar 

  41. McCague R, Rowlands MG: Conformational analysis of the aromatase inhibitor 3-ethyl-3-(4-pyridyl)-piperidine-2,6-dione (rogletimide) and discovery of potent 5-alkyl derivatives. J Med Chem 35:3699–3704, 1992

    Google Scholar 

  42. Laughton CA, McKenna R, Neidle S, Jarman M, McCague R, Rowlands MG: Crystallographic and molecular modeling studies on 3-ethyl-3-(4-pyridyl)-piperidine-2,6-dione and its butyl analogue, inhibitors of mammalian aromatase. Comparison with natural substrates: prediction of enantioselectivity forN-alkyl derivatives. J Med Chem 33:2673–2679, 1990

    Google Scholar 

  43. Hartmann RW, Batzl C: Aromatase inhibitors. Synthesis and evaluation of mammary tumor inhibiting activity of 3-alkylated 3-(4-aminophenyl)piperidine-2,6-diones. J Med Chem 29:1363–1369, 1986

    Google Scholar 

  44. Hartmann RW, Batzl C, Pongratz TM, Mannschreck A: Synthesis and aromatase inhibition of 3-cycloalkyl-substituted 3-(4-aminophenyl)piperidine-2,6-diones. J Med Chem 35:2210–2214, 1992

    Google Scholar 

  45. Kellis JT, Vickery LE: Inhibition of estrogen synthase (aromatase) by 4-cyclohexylaniline. Endocrinology 114:2128–2137, 1984

    Google Scholar 

  46. Vanden Bossche H, Marichal P, Moereels H: Molecular mechanisms of antifungal activity and fungal resistance: focus on inhibitors of ergosterol biosynthesis.In: Maresca B, Kobayashi GS, Yamaguchi H (eds) Molecular Biology and its Application in Medical Mycology. Springer-Verlag, Berlin, 1993, p 179–197

    Google Scholar 

  47. Vanden Bossche H, Marichal P: Mode of action of anti-Candida drugs: Focus on terconazole and other ergosterol biosynthesis inhibitors. Am J Obstet Gynecol 165:1193–1199, 1991

    Google Scholar 

  48. Mason JI, Carr BR, Murray BA: Imidazole antimycotics: selective inhibitors of steroid aromatization and progesterone hydroxylation. Steroids 50:179–189, 1987

    Google Scholar 

  49. Vanden Bossche H: Inhibitors of P450-dependent steroid biosynthesis: from research to medical treatment. J Steroid Biochem Mol Biol 43:1003–1021, 1992

    Google Scholar 

  50. Steele RE, Mellor LB, Sawyer WK, Wasvary JM, Browne RE:In vitro andin vivo studies demonstrating potent and selective estrogen inhibition with the nonsteroidal aromatase inhibitor CGS16949A. Steroids 50:147–161, 1987

    Google Scholar 

  51. Bhatnagar AS, Häusler A, Schieweck K, Browne LJ, Bowman R, Steele RE: Novel aromatase inhibitors. J Steroid Biochem Mol Biol 37:363–367, 1990

    Google Scholar 

  52. Browne LJ, Gude C, Rodriguez H, Steele RE, Bhatnagar A: Fadrozole hydrochloride: a potent, selective, nonsteroidal inhibitor of aromatase for the treatment of estrogen-dependent disease. J Med Chem 34:725–736, 1991

    Google Scholar 

  53. Kadohama N, Yarborough C, Zhou D, Chen S, Osaw Y: Kinetic properties of aromatase mutants Pro 308 Phe, Asp 309 Asn, and Asp 309 Ala and their interactions with aromatase inhibitors. J Steroid Biochem Mol Biol 43:693–701, 1992

    Google Scholar 

  54. Furet P, Batzl C, Bhatnagar A, Francotte E, Lang M: Aromatase inhibitors: synthesis, biological activity, and binding mode of azole type compounds. J Med Chem 36:1393–1400, 1993

    Google Scholar 

  55. Lamberts SWJ, Bruining HA, Marzouk H, Zuiderwijk J, Uitterlinden P, Blijd JJ, Hacking WHL, De Jong FH: The new aromatase inhibitor CGS-16949A suppresses aldosterone and cortisol production by human adrenal cellsin vitro. J Clin Metab 69:896–901, 1989

    Google Scholar 

  56. Santen RJ, Demers LM, Adlercreutz H, Harvey HA, Santner S, Sanders S, Lipton A: Inhibition of aromatase with CGS16949A in post-menopausal women. J Clin Endocrinol Metab 68:99–106, 1989

    Google Scholar 

  57. Demers LM, Melby JC, Wilson TE, Lipton A, Harvey HA, Santen RJ: The effects of CGS 16949A, an aromatase inhibitor, on adrenal mineralocorticoid biosynthesis. J Clin Endocrinol Metab 70:1162–1166, 1990

    Google Scholar 

  58. Lipton A, Harvey HA, Demers LM, Hanagan JR, Mulagha MT, Kochak GM, Fitzsimmons S, Sanders SI, Santen RJ: A phase I trial of CGS 16949A, a new aromatase inhibitor. Cancer 65:1279–1285, 1990

    Google Scholar 

  59. Dowsett M, Stein RC, Mehta A, Coombes RC: Potency and selectivity of the non-steroidal aromatase inhibitor CGS 16949A in postmenopausal breast cancer patients. Clin Endocrinol 32:623–634, 1990

    Google Scholar 

  60. Raats JI, Falkson G, Falkson HC: A study of fadrozole, a new aromatase inhibitor, in postmenopausal women with advanced metastatic breast cancer. J Clin Oncol 10:111–116, 1992

    Google Scholar 

  61. Geelen JAA, Loozen HJJ, Deckers GH, De Leeuw R, Kloosterboer HJ, Lamberts SWJ: ORG 33201: a new highly selective orally active aromatase inhibitor. J Steroid Biochem Mol Biol 44:681–682, 1993

    Google Scholar 

  62. Vanden Bossche H, Willemsens G, Roels I, Bellens D, Moereels H, Coene MC, LeJeune L, Lauwers W, Janssen PAJ: R 76 713 and enantiomers: selective, nonsteroidal inhibitors of the cytochrome P450-dependent estrogen synthesis. Biochem Pharmacol 40:1707–1718, 1990

    Google Scholar 

  63. Krekels MDWG, Wouters W, De Coster R: Aromatase inhibition by R 76 713: a kinetic analysis in rat ovarian homogenates. Steroids 55:69–73, 1990

    Google Scholar 

  64. Wouters W, De Coster R, Krekels M, Van Dun J, Beerens D, Haelterman C, Raeymaekers A, Freyne E, Van Gelder J, Venet M, Janssen PAJ: R 76 713, a new specific non-steroidal aromatase inhibitor. J Steroid Biochem 32:781–788, 1989

    Google Scholar 

  65. De Coster R, Wouters W, Bowden CR, Vanden Bossche H, Bruynseels J, Tuman RW, Van Ginckel R, Snoeck E, Van Peer A, Janssen PAJ: New nonsteroidal aromatase inhibitors: focus on R 76 713. J Steroid Biochem Mol Biol 37:335–341, 1990

    Google Scholar 

  66. Krekels MDWG, Wouters W, De Coster R, Van Ginckel R, Leonaers A, Janssen PAJ: Aromatase in human choriocarcinoma JEG-3: inhibition by R 76 713 in cultured cells and in tumors grown in nude mice. J Steroid Biochem Mol Biol 38:415–422, 1991

    Google Scholar 

  67. Wouters W, De Coster R, Beerens D, Doolaege R, Guiwez JA, Van Camp K, Vanden Pas H, Van Herendael B: Potency and selectivity of the aromatase inhibitor R 76 713. A study of ovarian, adipose, stromal, testicular and adrenal cells. J Steroid Biochem 36:57–65, 1990

    Google Scholar 

  68. Kadohama N, Zhou D, Chen S, Osawa Y: Catalytic efficiency of expressed aromatase following sitedirected mutagenesis. Biochim Biophys Acta 1163: 195–200, 1993

    Google Scholar 

  69. Vanden Bossche H, Willemsens G, Bellens D, Roels I, Janssen PAJ: From 14α-demethylase inhibitors in fungal cells to androgen and oestrogen biosynthesis inhibitors in mammalian cells. Biochem Soc Trans 18:10–13, 1990

    Google Scholar 

  70. Moereels H, De Bie L, Tollenaere JP: CGEMA and VGAP: a colour graphics editor for multiple alignment using a variable gap penalty. Application to the muscarinic acetylcholine receptor. J Comput Aided Mol Design 4:131–145, 1990

    Google Scholar 

  71. Dukes M, Edwards PN, Large M, Smith IK, Frank R, Yatesj RA, Deberardinis M, Plourde PV: ICI D1033, a new, selective, non-steroidal aromatase inhibitor (Abstract). 3rd International Conference on Aromatase, Bologna, June 14–17, 1992

    Google Scholar 

  72. Bhatnagar AS, Häusler A, Schieweck K, Lang M, Bowman R: Highly selective inhibition of estrogen biosynthesis by CGS 20267, a new non-steroidal aromatase inhibitor. J Steroid Biochem Mol Biol 37:1021–1027, 1990

    Google Scholar 

  73. Schiewick K, Bhatnagar AS, Batzl Ch, Lang M: Anti-tumor and endocrine effects of non-steroidal aromatase inhibitors on estrogen-dependent rat mammary tumors. J Steroid Biochem Mol Biol 44:633–636, 1993

    Google Scholar 

  74. Lang M, Batzl Ch, Furet P, Bowman R, Häusler A, Bhatnagar AS: Structure-activity relationships and binding model of novel aromatase inhibitors. J Steroid Biochem Mol Biol 44:421–428, 1993

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Departments of Comparative Biochemistry, Janssen Research Foundation, B-2340, Beerse, Belgium

    Hugo Vanden Bossche

  2. Theoretical Medicinal Chemistry, Janssen Research Foundation, B-2340, Beerse, Belgium

    Henri Moereels & Luc M. H. Koymans

Authors
  1. Hugo Vanden Bossche
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Henri Moereels
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Luc M. H. Koymans
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bossche, H.V., Moereels, H. & Koymans, L.M.H. Aromatase inhibitors — mechanisms for non-steroidal inhibitors. Breast Cancer Res Tr 30, 43–55 (1994). https://doi.org/10.1007/BF00682740

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00682740

Key words

Search

Navigation