新的芳香化酶抑制剂。的合成和生物活性pyridyl-substituted萘满酮衍生品。

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拜耳H, Batzl C,哈特曼RW, Mannschreck

新的芳香化酶抑制剂。的合成和生物活性pyridyl-substituted萘满酮衍生品。

J地中海化学。1991年9月,34 (9):2685 - 91。

PubMed ID

1895288 (在PubMed

]

文摘

(E) - 2 - (4-pyridylmethylene) 1-tetralones 1 - 7 (1 H;2、5-OCH3;3,6-OCH3;4,7-OCH3;5,5-OH;6,6;7,7-OH)得到相应的醇醛缩合1-tetralones 4-pyridinecarboxaldehyde,的哦,后续醚化合物5和7的乳沟OCH3-substituted 2 - (4-pyridylmethylene) 1-tetralones。催化加氢的1 - 4给出了2 - (4-pyridylmethyl)第8 - 11 1-tetralones (8 H;9日,5-OCH3;10、6-OCH3; 11, 7-OCH3). Subsequent ether cleavage of 9-11 led to the corresponding OH compounds 12-14 (12, 5-OH; 13, 6-OH; 14, 7-OH). The enantiomers of 11 and 12 were separated semipreparatively by HPLC on triacetylcellulose. All compounds (1-14) showed an inhibition of human placental aromatase exhibiting relative potencies from 2.2 to 213 [compounds 6 and (+)-12, respectively; aromatase inhibitory potency of aminoglutethimide (AG) = 1]. The compounds exhibited no or only a weak inhibition of desmolase [cholesterol side chain cleavage enzyme; maximum activity shown by 12, 23% inhibition (25 microM); AG, 53% inhibition (25 microM)]. In vivo, however, the compounds were not superior to AG as far as the reduction of the plasma estradiol concentration and the mammary carcinoma (MC) inhibiting properties are concerned (PMSG-primed SD rats as well as DMBA-induced MC of the SD rat, pre- and postmenopausal experiments, and the transplantable MXT-MC of the BD2F1 mouse). This is due to a fast decrease of the plasma E2 concentration inhibiting effect as could be shown by a kinetic experiment. In addition, select compounds inhibited rat ovarian aromatase much less than human placental aromatase (12, factor of 10). Estrogenic effects as a cause for the poor in vivo activity of the test compounds could be excluded, since they did not show affinity for the estrogen receptor.

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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)	37000年	N /一个	N /一个	细节