Pyridyl-substituted tetrahydrocyclopropa[一]萘:P450 arom高活性和选择性抑制剂。

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哈特曼RW,拜耳H, Grun G, Sergejew T,巴茨U, Mitrenga M

Pyridyl-substituted tetrahydrocyclopropa[一]萘:P450 arom高活性和选择性抑制剂。

J地中海化学。1995年6月9日,38(12):2103 - 11所示。

PubMed ID

7783141 (在PubMed

]

文摘

的合成和生物评价取代exo-1——(4-pyridyl) 1、2、3、7 b-tetrahydro-1h-cyclopropa[一]萘年代雌激素生物合成抑制剂(描述H (1);4-OCH3 (2);5-OCH3 (3);6-OCH3 (4);1-CH3 6-OCH3 (5);4-OCH3 7-Br (6);6-OCH3 5-Br (7);哦(8);5-OH (9);6 (10))。 The synthetic key step--the formation of the cyclopropyl ring--was accomplished using the conditions of a modified Wolff-Kishner reduction (N2H5OH/KOH; delta T) and yielded exclusively the exo-configurated diastereomers. The racemic compounds 1-10 showed an inhibition of human placental aromatase (P450 arom) exhibiting relative potencies (rp) from 3.7 to 303 (compounds 8 and 4, respectively; rp of aminoglutethimide (AG) identical to 1, fadrozole = 359). The enantiomers of 4 and 7 were separated by LPLC on tribenzoyl cellulose and by crystallization of the diastereomeric tartrates (4). (1aS,2S,7bS)-(+)-4 (absolute configuration determined by X-ray crystallographic analysis) is the active P450 arom inhibiting enantiomer of 4 and shows a rp value of 617. Compound 4 is a reversible inhibitor showing a competitive type of inhibition and a type II difference spectrum. In vitro 4 influenced other steroidogenic P450 enzymes either not at all (bovine adrenal P450 scc) or only marginally (rat testicular P450 17, bovine adrenal P450 18). In ACTH-stimulated rat adrenal tissue, 4 was less active, inhibiting corticosterone and aldosterone formation compared to AG and fadrozole, respectively. In vivo 4 was not superior to AG as far as the inhibition of the uterotrophic activity of androstenedione (juvenile SD rats) and the reduction of the plasma estradiol concentration (pregnant mares' serum gonadotropin-primed SD rats) are concerned. Compound 4 shows marked antitumor activity in the dimethylbenzanthracene-induced mammary carcinoma of the SD rat: in the postmenopausal model it is at least as active as AG; in the premenopausal experiment it is clearly superior to AG. No induction of hepatic P450 enzymes was observed in the latter experiment. The rp value of 4 toward rat ovarian P450 arom, i.e., 23 (rp of AG identical to 1), is markedly decreased compared to the human enzyme (rp value of 303). From this fact it must be concluded that 4 should be more active in the human than in the rat.

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绑定属性

药物	目标	财产	测量	pH值	温度(°C)
氨鲁米特	细胞色素P450 19 a1	集成电路50 (nM)	18500年	N /一个	N /一个	细节