Английская Википедия:Amphenone B

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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,[1][2][3] as well as of cholesterol side-chain cleavage enzyme,[4][5] thereby inhibiting the production of steroid hormones including glucocorticoids, mineralocorticoids, androgens, and estrogens.[4][6] 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.[7][5][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),[4][10] which in 1949 had been found to selectively induce adrenal atrophy.[1][11][12] In contrast to p,p'-DDD, which has direct cytotoxic effects on the adrenal glands via an unknown mechanism,[1] 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.[1][2][4]

Amphenone B has also been found to produce progesterone-like progestogenic effects, including uterine hypertrophy and mammary lobuloalveolar development.[1][5][13][14] These effects occurred even in animals that had been ovariectomized and hypophysectomized, suggesting that amphenone B might be acting directly on the target organs.[1][5] 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.[1] Conversely, the progesterone-like effects of amphenone B on the mammary glands were found to persist even in adrenalectomized and ovariectomized animals.[5]

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.[1][15] 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,[15] as well as in decreasing circulating levels of androgens and estrogens.[1][6] Moreover, due to reduced aldosterone secretion, it caused marked diuresis and increased urinary sodium excretion.[2][13] 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,[7] 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.[2][4][11][15][13]

Subsequently, analogues of amphenone B with reduced toxicity and improved specificity were developed.[2][4][11] One of the most potent of these was metyrapone (2-methyl-1,2-di(pyridin-3-yl)propan-1-one),[11] a selective inhibitor of 11β-hydroxylase,[2][6] which was selected for clinical development and was eventually approved and marketed in 1958 as a diagnostic agent for Cushing's syndrome.[1][4][16] 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,[17][18] 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.[4] 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,[4][19] 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.[20][21][22] The drug was subsequently repurposed for use in the treatment of metastatic breast cancer and Cushing's syndrome.[20][22]

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.[2][13] As such, early publications of amphenone B, and some subsequent publications,[5] refer to the drug by the incorrect structure.[2]

See also

References

Шаблон:Reflist

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  1. ↑ 1,00 1,01 1,02 1,03 1,04 1,05 1,06 1,07 1,08 1,09 1,10 Шаблон:Cite book
  2. ↑ 2,0 2,1 2,2 2,3 2,4 2,5 2,6 2,7 2,8 Шаблон:Cite book
  3. ↑ Шаблон:Cite journal
  4. ↑ 4,0 4,1 4,2 4,3 4,4 4,5 4,6 4,7 4,8 Шаблон:Cite book
  5. ↑ 5,0 5,1 5,2 5,3 5,4 5,5 Шаблон:Cite book
  6. ↑ 6,0 6,1 6,2 Шаблон:Cite book
  7. ↑ 7,0 7,1 Шаблон:Cite journal
  8. ↑ Шаблон:Cite journal
  9. ↑ Шаблон:Cite book
  10. ↑ Шаблон:Cite book
  11. ↑ 11,0 11,1 11,2 11,3 Шаблон:Cite book
  12. ↑ Шаблон:Cite book
  13. ↑ 13,0 13,1 13,2 13,3 Шаблон:Cite book
  14. ↑ Шаблон:Cite book
  15. ↑ 15,0 15,1 15,2 Шаблон:Cite book
  16. ↑ Шаблон:Cite book
  17. ↑ Шаблон:Cite book
  18. ↑ Шаблон:Cite book
  19. ↑ Шаблон:Cite book
  20. ↑ 20,0 20,1 Шаблон:Cite book
  21. ↑ Шаблон:Cite book
  22. ↑ 22,0 22,1 Шаблон:Cite book
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