新型氧杂甾体作为孕酮受体拮抗剂的合成与鉴定
Synthesis and identification of novel oxa-steroids as progesterone receptor antagonists.
作者信息
Kang Fu-An, Allan George, Guan Jihua, Jain Nareshkumar, Linton Olivia, Tannenbaum Pamela, Xu Jun, Zhu Peifang, Gunnet Joseph, Chen Xin, Demarest Keith, Lundeen Scott, Sui Zhihua
机构信息
Johnson and Johnson Pharmaceutical Research and Development, LLC, 665 Stockton Drive, Exton, PA 19341, USA.
出版信息
Bioorg Med Chem Lett. 2007 Feb 15;17(4):907-10. doi: 10.1016/j.bmcl.2006.11.062. Epub 2006 Dec 1.
A novel series of oxa-steroids 6 derived from (8S, 13S, 14R)-7-oxa-estra-4,9-diene-3,17-dione 1 have been synthesized and identified as potent and selective progesterone receptor antagonists. These novel oxa-steroids showed similar potency to mifepristone. Preliminary SAR study resulted in the most potent 17-phenylethynyl oxa-steroid 6i wih an IC(50) of 1.4nM. In contrast to the equipotent mifepristone toward the progesterone receptor (PR) and glucocorticoid receptor (GR), compound 6i had over 200-fold selectivity for PR over GR.
一系列源自(8S, 13S, 14R)-7-氧杂-雌甾-4,9-二烯-3,17-二酮1的新型氧杂甾体6已被合成，并被鉴定为强效和选择性孕激素受体拮抗剂。这些新型氧杂甾体显示出与米非司酮相似的效力。初步的构效关系研究得到了最有效的17-苯乙炔基氧杂甾体6i，其IC(50)为1.4 nM。与对孕激素受体(PR)和糖皮质激素受体(GR)效力相当的米非司酮不同，化合物6i对PR的选择性比对GR高200倍以上。
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