Cook C E, Wani M C, Lee Y W, Fail P A, Petrow V
Research Triangle Institute, Research Triangle Park, NC 27709-2194.
Life Sci. 1993;52(2):155-62.
16 alpha-Ethyl-17 beta-acetyl substitution in the D-ring of steroids having an 11 beta-aryl-4,9-dien-3-one structure resulted in compounds with strong progestational activity. These compounds caused endometrial proliferation in the uterus of estrogen-primed rabbits with a potency greater than that of progesterone and had no detectable antiprogestational activity in this model. This is in stark contrast with the marked antiprogestational activity in rabbits, rats and humans reported for most 11 beta-aryl-4,9-diene-3-keto steroids such as RU 486 and its 17 beta-acetyl-17 alpha-acetoxy analog, 17 alpha-acetoxy-11 beta-(4-N,N-dimethylaminophenyl)-19-norpregna-4,9-diene- 3,20-dione. Examination of structure activity relationships in combination with computer aided molecular modelling suggests that a binding interaction of the 16 alpha-ethyl group with the progesterone receptor (PR) or the PR-progestin response element complex may play the major role in this reversal of activity profile.
在具有11β-芳基-4,9-二烯-3-酮结构的甾体D环中进行16α-乙基-17β-乙酰基取代，得到了具有强孕激素活性的化合物。这些化合物在雌激素预处理的兔子宫中引起子宫内膜增生，其效力大于孕酮，并且在该模型中未检测到抗孕激素活性。这与大多数11β-芳基-4,9-二烯-3-酮甾体（如RU 486及其17β-乙酰基-17α-乙酰氧基类似物、17α-乙酰氧基-11β-(4-N,N-二甲基氨基苯基)-19-去甲孕-4,9-二烯-3,20-二酮）在兔、大鼠和人类中报道的显著抗孕激素活性形成鲜明对比。结合计算机辅助分子建模对构效关系的研究表明，16α-乙基基团与孕激素受体（PR）或PR-孕激素反应元件复合物的结合相互作用可能在这种活性谱的逆转中起主要作用。
