Development of 1,3-diphenyladamantane derivatives as nonsteroidal progesterone receptor antagonists.
Development of 1,3-diphenyladamantane derivatives as nonsteroidal progesterone receptor antagonists.
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DOI：
10.1016/j.bmc.2014.12.047
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发表时间：
2015-02
影响因子：
3.5
通讯作者：
Shuichi Mori;Yuki Takeuchi;Aya Tanatani;H. Kagechika;S. Fujii
中科院分区：
文献类型：
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作者：
Shuichi Mori;Yuki Takeuchi;Aya Tanatani;H. Kagechika;S. Fujii
非甾体孕酮受体（PR）完全拮抗剂需要作为阐明PR的生理功能的工具和作为治疗各种疾病的候选药物。我们设计并合成了1，3-二苯基金刚烷衍生物，并与我们最近开发的基于硼簇的PR拮抗剂进行了比较，研究了它们的PR拮抗活性。在合成的金刚烷衍生物中，化合物9a表现出最有效的PR-拮抗活性（IC 50：25 nM），并显示出与基于硼簇的PR拮抗剂相当的对PR配体结合结构域的高结合亲和力。这些结果表明，二取代的金刚烷，像硼簇-碳硼烷，是一个有前途的疏水药效团，为进一步的非甾体PR拮抗剂的结构发展。
Nonsteroidal progesterone receptor (PR) full antagonists are needed as tools for elucidating the physiological functions of PR and as candidates for treatment of various diseases. We designed and synthesized 1,3-diphenyladamantane derivatives, and investigated their PR-antagonistic activity in comparison with our recently developed boron cluster-based PR antagonists. Among the synthesized adamantane derivatives, compound9aexhibited the most potent PR-antagonistic activity (IC50: 25 nM) and showed high binding affinity for the PR ligand-binding domain, comparable with that of the boron cluster-based PR antagonists. These results suggest that disubstituted adamantane, like the boron clusterm-carborane, is a promising hydrophobic pharmacophore for further structural development of nonsteroidal PR antagonists.