Citation: Yan-Hui Zhu, Meng Zhang, Qun-Yi Li, Qing Liu, Jie Zhang, Yun-Yun Yuan, Fa-Jun Nan, Ming-Wei Wang. The hit-to-lead optimization of 1, 2, 3, 4, 4a, 9a-hexahydro-1H-xanthenes as glucocorticoid receptor antagonists[J]. Chinese Chemical Letters, ;2014, 25(05): 693-698. doi: 10.1016/j.cclet.2014.03.017 shu

The hit-to-lead optimization of 1, 2, 3, 4, 4a, 9a-hexahydro-1H-xanthenes as glucocorticoid receptor antagonists

Yan-Hui Zhu ^a ,
Meng Zhang ^a ,
Qun-Yi Li ^a ,
Qing Liu ^a,b ,
Jie Zhang ^a ,
Yun-Yun Yuan ^a ,
Fa-Jun Nan ^a,b ,
Ming-Wei Wang ^a,b,,

1.
a The National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China;
2.
b The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China

Corresponding author: Ming-Wei Wang,
Received Date: 6 November 2013
Available Online: 20 February 2014
Fund Project:

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.
- Glucocorticoid receptor,
- Antagonist,
- 1,2,3,4,4a,9a-Hexahydroxanthene,
- Structure-activity relationship,
- Lead optimization
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