Amphenone B Explained

Amphenone B, or simply amphenone, also known as 3,3-bis(p-aminophenyl)butan-2-one, is an inhibitor of steroid hormone and thyroid hormone biosynthesis which was never marketed but has been used as a tool in scientific research to study corticosteroids and the adrenal glands.[1] [2] It acts as competitive inhibitor of 11β-hydroxylase, 17α-hydroxylase, 17,20-lyase, 21-hydroxylase, and 3β-hydroxysteroid dehydrogenase,[3] as well as of cholesterol side-chain cleavage enzyme, thereby inhibiting the production of steroid hormones including glucocorticoids, mineralocorticoids, androgens, and estrogens.[4] [5] In addition, amphenone B inhibits the production of thyroxine by a thiouracil-like mechanism, specifically via inhibition of organic binding of iodine and uptake of iodide by the thyroid gland.[6] [7] [8] [9]

Amphenone B was first synthesized in 1950 and is a diphenylmethane derivative that was derived from the insecticide 2,2-di(p-chlorophenyl)-1,1-dichloroethane (p,p'-DDD),[10] which in 1949 had been found to selectively induce adrenal atrophy.[11] [12] In contrast to p,p'-DDD, which has direct cytotoxic effects on the adrenal glands via an unknown mechanism, amphenone B does not have cytotoxic effects, and instead causes adrenal and thyroid gland hypertrophy due to respective inhibition of corticosteroid and thyroxine biosynthesis, subsequent loss of negative feedback on the hypothalamic-pituitary-adrenal and hypothalamic-pituitary-thyroid axes, and consequent hypersecretion of adrenocorticotropic hormone (ACTH) and thyroid-stimulating hormone (TSH) from the pituitary gland.

Amphenone B has also been found to produce progesterone-like progestogenic effects, including uterine hypertrophy and mammary lobuloalveolar development.[13] These effects occurred even in animals that had been ovariectomized and hypophysectomized, suggesting that amphenone B might be acting directly on the target organs. However, it was found that adrenalectomy abolished the progesterone-like effects of amphenone B on the uterus, whereas those of progesterone were retained in the same experimental conditions, supporting the notion that amphenone B was not actually acting directly on the uterus. Conversely, the progesterone-like effects of amphenone B on the mammary glands were found to persist even in adrenalectomized and ovariectomized animals.

Amphenone B was tested in humans in the mid-1950s as a potential treatment for cortisol-dependent conditions such as Cushing's syndrome and adrenocortical carcinoma.[14] In healthy subjects and patients with adrenocortical carcinoma, the drug was found to be effective in decreasing circulating levels of corticosteroids including cortisol, corticosterone, and aldosterone, as well as in decreasing circulating levels of androgens and estrogens. Moreover, due to reduced aldosterone secretion, it caused marked diuresis and increased urinary sodium excretion. Unfortunately, amphenone B also caused many side effects, some severe, including drowsiness, gastrointestinal disturbances such as heartburn, nausea, and vomiting, morbilliform and pruritic rashes, methemoglobinemia, and hepatotoxicity including impaired liver function and hepatomegaly, and these toxicities, as well as the diversity of its effects on various organs (e.g., also possessing antithyroid and even anesthetic activity), precluded its therapeutic use.

Subsequently, analogues of amphenone B with reduced toxicity and improved specificity were developed. One of the most potent of these was metyrapone (2-methyl-1,2-di(pyridin-3-yl)propan-1-one), a selective inhibitor of 11β-hydroxylase, which was selected for clinical development and was eventually approved and marketed in 1958 as a diagnostic agent for Cushing's syndrome.[15] Another was mitotane (o,p'-DDD, or 1,1-(dichlorodiphenyl)-2,2-dichloroethane), an inhibitor of cholesterol side-chain cleavage enzyme and to a lesser extent of other steroidogenic enzymes,[16] [17] which additionally has selective and direct cytotoxic effects on the adrenal glands similarly to p,p'-DDD, and was introduced in 1960 for the treatment of adrenocortical carcinoma. Aminoglutethimide (3-(4-aminophenyl)-3-ethylpiperidine-2,6-dione), which was originally introduced as an anticonvulsant in 1960, is closely related structurally to amphenone B,[18] and following its introduction, was found to cause adrenal insufficiency in patients due to inhibition of cholesterol side-chain cleavage enzyme and suppression of corticosteroid production.[19] [20] [21] The drug was subsequently repurposed for use in the treatment of metastatic breast cancer and Cushing's syndrome.

Amphenone B was originally thought to be 1,2-bis(p-aminophenyl)-2-methylpropan-1-one, but it was discovered in 1957 that the synthesis of amphenone B was accompanied by an unexpected molecular rearrangement and that the drug was actually 3,3-bis-(p-aminophenyl)butan-2-one.[22] As such, early publications of amphenone B, and some subsequent publications, refer to the drug by the incorrect structure.

See also

Notes and References

  1. Book: Tullner WW . Nonhormal Inhibitors of Adrenocortical Steroid Biosynthesis . Martini L . Hormonal Steroids Biochemistry, Pharmacology, and Therapeutics: Proceedings of the First International Congress on Hormonal Steroids. https://books.google.com/books?id=wXCjz1JDTpUC&pg=PA383. 2 December 2012. Elsevier. 978-0-323-14465-0. 383, 387, 394, 399, 402.
  2. Book: Whitehouse MW . Drugs, Hormone, and Other Factors Influencing Steroid and Sterol Metabolism . Paoletti R . Lipid Pharmacology. https://books.google.com/books?id=NSRY73S97DAC&pg=PA217. 2 December 2012. Elsevier Science. 978-0-323-15511-3. 217–219.
  3. Hiroshi I, Bun-Ichi T . Studies on enzyme reactions related to steroid biosynthesis: II. Submicrosomal distribution of the enzymes related to androgen production from pregnenolone and of the cytochrome P-450 in testicular gland of rat. . Journal of Steroid Biochemistry . April 1970 . 1 . 2 . 83–6 . 10.1016/0022-4731(70)90003-8 .
  4. Book: Bentley PJ . Steroid Hormones: Introduction . Endocrine Pharmacology: Physiological Basis and Therapeutic Applications. https://books.google.com/books?id=W6M9AAAAIAAJ&pg=PA143. 1980. CUP Archive. 978-0-521-22673-8. 143, 162–163.
  5. Book: Dorfman RI . Inhibitors of Steroid Actions and Cholesterol and Steroid Biosynthesis . Hochster R . Metabolic Inhibitors V1: A Comprehensive Treatise. https://books.google.com/books?id=n3vAYKkEXkEC&pg=PA578. 2 December 2012. Elsevier. 978-0-323-14338-7. 578–.
  6. ATHLETE'S foot . British Medical Journal . 1 . 5021 . 755–756 . March 1957 . 13404297 . 1974747 . 10.1136/bmj.1.5021.754 .
  7. Book: Costoff A . Adrenocorticotropes . Ultrastructure of Rat Adenohypophysis: Correlation with Function. https://books.google.com/books?id=dw8vKtw_V8QC&pg=PA82. 2 December 2012. Elsevier Science. 978-0-323-15957-9. 82–86.
  8. Jawetz E, Gunnison JB . vanc . Quantitative aspects of antibiotic synergism and antagonism. The American Journal of Medicine. 13. 1. 1952. 95. 0002-9343. 10.1016/0002-9343(52)90099-5. [...] concentration in the gland was observed after administration of amphenone “B.” Radioiodine concentrations were found to be approximately 10 per cent of the control values. Further in viva and in vitro experiments have shown that this is most probably due to a thiouracil-type of [...].
  9. Book: Sarne D . Effects of the Environment, Chemicals and Drugs on Thyroid Function. . 27 September 2016 . De Groot LJ, Chrousos G, Dungan K, etal . Endotext [Internet]. . South Dartmouth (MA) . MDText.com, Inc. . 25905415 . https://www.ncbi.nlm.nih.gov/books/NBK285560/ .
  10. Book: Thomas JA, Keenan EJ . Effects of drugs on the endocrine system . Principles of Endocrine Pharmacology. https://books.google.com/books?id=mTagBQAAQBAJ&pg=PA280. 6 December 2012. Springer Science & Business Media. 978-1-4684-5036-1. 280–.
  11. Book: Heller H, Ginsburg M . Diuretic Drugs: Inhibitors of aldosterone secretion . Progress in Medicinal Chemistry. https://books.google.com/books?id=gstQfHtDsf0C&pg=PA173. 1 January 1961. 1 . Butterworth-Heinemann. 978-0-08-086249-1. 173– . 10.1016/S0079-6468(08)70389-8 . 13713109 .
  12. Book: Gold EM, Ganong WF . Effects of Drugs on Neuroendocrine Processes . Martini L, Ganong WG . Neuroendocrinology. https://books.google.com/books?id=SPcgBQAAQBAJ&pg=PA383. 22 October 2013. Elsevier. 978-1-4832-7505-5. 383–.
  13. Book: Deane HW . The anatomy, chemistry, and physiology of adrenocortical tissue, Inhibitors of adrenocortical function . The Adrenocortical Hormones: Their Origin · Chemistry, Physiology, and Pharmacology. https://books.google.com/books?id=BLXoCAAAQBAJ&pg=PA136. 27 November 2013. Springer Science & Business Media. 978-3-642-88385-9. 136– . 10.1007/978-3-642-88385-9_1 .
  14. Book: Neher R, Kahnt FW . Modifiers of Adrenocortical Function . Brodie BB, Gillette JR . Drugs and Enzymes: Proceedings of the Second International Pharmacological Meeting. https://books.google.com/books?id=UhMlBQAAQBAJ&pg=PA215. 22 October 2013. Elsevier. 978-1-4832-2351-3. 215–.
  15. Book: Kannan CR . Cushing's Syndrome . The Adrenal Gland. https://books.google.com/books?id=WqXSBwAAQBAJ&pg=PA161. 6 December 2012. Springer Science & Business Media. 978-1-4613-1001-3. 161–.
  16. Book: Cavagnini F, Giraldi FP . Adrenal Causes of Hypercortisolism . Jameson JL, De Groot LJ . Endocrinology - E-Book: Adult and Pediatric. https://books.google.com/books?id=W4dZ-URK8ZoC&pg=PA1888. 18 May 2010. Elsevier Health Sciences. 978-1-4557-1126-0. 1888–.
  17. Book: Tzanela M, Vassiliadi DA, Tsagarakis S . Coincidental adrenal masses and adrenal cancer . Harris PE, Bouloux PM . Endocrinology in Clinical Practice, Second Edition. https://books.google.com/books?id=tZE-AwAAQBAJ&pg=PA216. 24 March 2014. CRC Press. 978-1-84184-951-5. 216–.
  18. Book: Langer P, Greer MA . Antithyroid Substances and Naturally Occurring Goitrogens. 1977. S. Karger. 978-3-8055-2659-3.
  19. Book: Jackson IM . Aminoglutethimide (Orimeten): The present and the future . Harrap KR, Davis W, Calvert AH . Cancer Chemotherapy and Selective Drug Development: Proceedings of the 10th Anniversary Meeting of the Coordinating Committee for Human Tumour Investigations, Brighton, England, October 24–28, 1983. https://books.google.com/books?id=y3bjBwAAQBAJ&pg=PA481. 6 December 2012. Springer Science & Business Media. 978-1-4613-3837-6. 481–.
  20. Book: Selye H . Stressors and Conditioning Agents . Stress in Health and Disease. https://books.google.com/books?id=wrfYBAAAQBAJ&pg=PA57. 22 October 2013. Elsevier Science. 978-1-4831-9221-5. 57–.
  21. Book: Zak F . Lipid Hyperplasia, Adrenal Cortex, Rat . Jones TC, Mohr U, Hunt RD . Endocrine System. https://books.google.com/books?id=UTfvCAAAQBAJ&pg=PA83. 6 December 2012. Springer Science & Business Media. 978-3-642-96720-7. 83–.
  22. Book: Beyer KH, Baer JE . Newer diuretics. . Fortschritte der Arzneimittelforschung/Progress in Drug Research/Progrès des recherches pharmaceutiques . 1960 . 9–69 . Birkhäuser . Basel . https://books.google.com/books?id=kWT0BwAAQBAJ&pg=PA40 . 978-3-0348-7038-2 .

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