Center for Organic and Medicinal Chemistry, Research Triangle Institute, Research Triangle Park, NC 27709-2194, USA.
Bioorg Med Chem Lett. 2012 Feb 15;22(4):1705-8. doi: 10.1016/j.bmcl.2011.12.110. Epub 2011 Dec 30.
Early studies led to the identification of 11β-aryl-4',5'-dihydrospiro[estra-4,9-diene-17β,4'-oxazole] analogs with potent and more selective antiprogestational activity compared to antiglucocorticoid activity than mifepristone. In the present study, we replaced the 4'-dimethylaminophenyl group of mifepristone with the benzoxazol group to give 5a-d. We also prepared the 17β-formamido analogs 6a,b using a new synthetic strategy via the intermediate epoxide 21. These compounds were evaluated for their antagonist hormonal properties using the T47D cell-based alkaline phosphatase assay and the A549 cell-based functional assay. Compound 5c showed potent antagonist activity at GR with better selectivity for GR versus PR than mifepristone and is a promising lead for further development.
早期研究鉴定出了 11β-芳基-4'，5'-二氢螺[雌甾-4,9-二烯-17β，4'-恶唑]类似物，与米非司酮相比，其具有更强的抗孕激素活性和更高的选择性，而抗糖皮质激素活性较低。在本研究中，我们用苯并恶唑基取代米非司酮的 4'-二甲氨基苯基，得到 5a-d。我们还使用新的合成策略通过中间体环氧化物 21 制备了 17β-甲酰胺基类似物 6a,b。这些化合物通过 T47D 细胞碱性磷酸酶测定和 A549 细胞功能测定来评估其作为激素拮抗剂的特性。化合物 5c 对 GR 表现出很强的拮抗活性，对 GR 相对于 PR 的选择性优于米非司酮，是进一步开发的有前途的先导化合物。
