Design, synthesis, and evaluation of non-steroidal farnesoid X receptor (FXR) antagonist
Design, synthesis, and evaluation of non-steroidal farnesoid X receptor (FXR) antagonist
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DOI：
10.1016/j.bmc.2007.01.046
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发表时间：
2007-04-01
影响因子：
3.5
通讯作者：
Miyachi, Hiroyuki
中科院分区：
文献类型：
--
作者：
Kainuma, Masahiko;Makishima, Makoto;Miyachi, Hiroyuki
基于我们先前提出的配体超家族概念，制备了一系列取代的异恶唑衍生物作为候选的法尼醇X受体（FXR）拮抗剂。构效关系研究表明，异恶唑环5位取代基的形状和结构体积影响FXR拮抗活性。化合物15 g（5-取代基：2-萘基）和15 h（5-取代基：4-联苯基）被鉴定为对FXR的选择性高于孕酮受体的有效拮抗剂，其选择性高于天然存在的FXR拮抗剂GS。5-取代基也是这类FXR拮抗剂的特征性辅阻遏物募集概况的关键决定因素，尽管似乎涉及不同的机制：15 h稳定辅阻遏物-核受体相互作用，而15 g抑制辅激活物募集。(c)2007爱思唯尔有限公司版权所有。
A series of substituted-isoxazole derivatives was prepared as candidate farnesoid X receptor (FXR) antagonists, based on our previously proposed ligand superfamily concept. Structure-activity relationship studies indicated that the shape and the structural bulkiness of the substituent at the 5-position of the isoxazole ring affected FXR-antagonistic activity. Compounds 15g (5-substituent: 2-naphthyl) and 15h (5-substituent: 4-biphenyl) were identified as potent antagonists with higher selectivity for FXR over progesterone receptor than the naturally occurring FXR antagonist GS. The 5-substituent is also a critical determinant of the characteristic corepressor recruitment profile of this class of FXR antagonists, though distinct mechanisms appear to be involved: 15h stabilizes the corepressor-nuclear receptor interaction, while 15g inhibits coactivator recruitment. (c) 2007 Elsevier Ltd. All rights reserved.