Abstract
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.
| Original language | English |
|---|---|
| Pages (from-to) | 2587-2600 |
| Number of pages | 14 |
| Journal | Bioorganic and Medicinal Chemistry |
| Volume | 15 |
| Issue number | 7 |
| DOIs | |
| Publication status | Published - Apr 1 2007 |
| Externally published | Yes |
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Keywords
- Corepressor
- Farnesoid X receptor
- FXR
- FXR antagonist
- Non-steroidal
ASJC Scopus subject areas
- Biochemistry
- Molecular Biology
- Organic Chemistry
- Drug Discovery
- Pharmaceutical Science
Cite this
Design, synthesis, and evaluation of non-steroidal farnesoid X receptor (FXR) antagonist. / Kainuma, Masahiko; Makishima, Makoto; Hashimoto, Yuichi; Miyachi, Hiroyuki.
In: Bioorganic and Medicinal Chemistry, Vol. 15, No. 7, 01.04.2007, p. 2587-2600.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Design, synthesis, and evaluation of non-steroidal farnesoid X receptor (FXR) antagonist
AU - Kainuma, Masahiko
AU - Makishima, Makoto
AU - Hashimoto, Yuichi
AU - Miyachi, Hiroyuki
PY - 2007/4/1
Y1 - 2007/4/1
N2 - 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.
AB - 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.
KW - Corepressor
KW - Farnesoid X receptor
KW - FXR
KW - FXR antagonist
KW - Non-steroidal
UR - http://www.scopus.com/inward/record.url?scp=33847780436&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=33847780436&partnerID=8YFLogxK
U2 - 10.1016/j.bmc.2007.01.046
DO - 10.1016/j.bmc.2007.01.046
M3 - Article
C2 - 17292610
AN - SCOPUS:33847780436
VL - 15
SP - 2587
EP - 2600
JO - Bioorganic and Medicinal Chemistry
JF - Bioorganic and Medicinal Chemistry
SN - 0968-0896
IS - 7
ER -