Discovery and optimization of 1, 3, 4-trisubstituted-pyrazolone derivatives as novel, potent, and nonsteroidal farnesoid X receptor (FXR) selective antagonists

…, X Xu, H Jin, W Yan, R Ma, J Zhu, X Shen…

Index: Huang, Huang; Yu, Ying; Gao, Zhenting; Jin, Hui; Yan, Wenzhong; Ma, Ruoqun; Zhu, Jin; Shen, Xu; Jiang, Hualiang; Li, Jian; Li, Chenjing; Xu, Xing; Chen, Lili; Zhang, Yong Journal of Medicinal Chemistry, 2012 , vol. 55, # 16 p. 7037 - 7053,17 Title/Abstract Full Text Show Details Huang, Huang; Yu, Ying; Gao, Zhenting; Zhang, Yong; Li, Chenjing; Xu, Xing; Jin, Hui; Yan, Wenzhong; Ma, Ruoqun; Zhu, Jin; Shen, Xu; Jiang, Hualiang; Chen, Lili; Li, Jian Journal of Medicinal Chemistry, 2012 , vol. 55, # 16 p. 7037 - 7053

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Citation Number: 36

Abstract

LBVS of 12480 in-house compounds, followed by HTRF assay, resulted in one nonsteroidal compound (11) with antagonistic activity against FXR (69.01±11.75 μM). On the basis of 11, 26 new derivatives (12a–z) were designed and synthesized accordingly. Five derivatives (12f–g, 12p, 12u, and 12y) showed better antagonistic activities against FXR than compound 11. Remarkably, the most potent derivative, 12u (8.96±3.62 μM), showed antagonistic ...