Discovery and SAR study of 3-(tert-butyl)-4-hydroxyphenyl benzoate and benzamide derivatives as novel farnesoid X receptor (FXR) antagonists.
3-(tert-Butyl)-4-hydroxyphenyl 2,4-dichlorobenzoate (1) was discovered in our in-house high throughput screening as a moderate FXR antagonist. To improve the potency and the stability of the hit 1, forty derivatives were synthesized and SAR was systematically explored. The results turn out that replacing the 2,4-dichlorophenyl with 2,6-dichloro-4-amidophenyl shows great improvement in potency, replacing the benzoate with benzamide shows improvement in stability and slight declining of potency and 3-(tert-butyl)-4-hydroxyphenyl unit is essential in obtaining the FXR antagonistic activity.
Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, PR China.
Kebiao
K
Song
Shanghai Research Center for Modernization of Traditional Chinese Medicine, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, PR China; Shanghai Key Laboratory for Bone and Joint Diseases, Shanghai Institute of Traumatology and Orthopaedics, Shanghai Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, PR China.
Xing
X
Xu
Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, PR China.
Peng
P
Liu
Shanghai Research Center for Modernization of Traditional Chinese Medicine, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, PR China.
Lili
L
Chen
Shanghai Research Center for Modernization of Traditional Chinese Medicine, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, PR China.
Xu
X
Shen
Shanghai Research Center for Modernization of Traditional Chinese Medicine, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, PR China. Electronic address: liujunhua1985@126.com.
Junhua
J
Liu
Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, PR China; Shanghai Research Center for Modernization of Traditional Chinese Medicine, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, PR China. Electronic address: lhhu@simm.ac.cn.
Lihong
L
Hu
D001549:Benzamides / Q000737:chemistry* / Q000378:metabolism; D001565:Benzoates / Q000737:chemistry* / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D006801:Humans; D011485:Protein Binding; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D000099150:Receptor, Farnesoid X-Activated
D001549:Benzamides; D001565:Benzoates; D018160:Receptors, Cytoplasmic and Nuclear; D000099150:Receptor, Farnesoid X-Activated; C037689:benzamide
FXR; FXR antagonist; Non-steroidal; SAR study