- The hit-to-lead optimization of 1,2,3,4,4a,9a-hexahydro-1H-xanthenes as glucocorticoid receptor antagonists
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The structure-activity relationship (SAR) study of a 1,2,3,4,4a,9a- hexahydro-1H-xanthene series of selective, human glucocorticoid receptor α (hGRα) antagonists is reported. Compounds were screened using hydroxyapatite-based GR binding and MMTV-Luc co-transfection reporter gene assays. Four different regions of the scaffold were modified to assess the effects on hGRα antagonism and related potency. Compound 8d exhibits an 8-fold better bioactivity than the original hit 1a, as well as an improved chemical stability, which make it a promising lead for the subsequent optimization.
- Zhu, Yan-Hui,Zhang, Meng,Li, Qun-Yi,Liu, Qing,Zhang, Jie,Yuan, Yun-Yun,Nan, Fa-Jun,Wang, Ming-Wei
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p. 693 - 698
(2014/06/09)
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