Discovery and SAR study of hydroxyacetophenone derivatives as potent,non-steroidal farnesoid X receptor (FXR) antagonists |
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| Institution: | 1. Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, PR China;2. Shanghai Research Center for Modernization of Traditional Chinese Medicine, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, PR China;1. Biogen, 250 Binney St., Cambridge, MA 02142, USA;2. Keimyung University, 1095 Dalgubeoldaero, Dalseo-Gu, Daegu, Republic of Korea;1. Academy of Scientific and Innovative Research, CSIR-Indian Institute of Chemical Technology, Hyderabad 500007, India;2. Natural Products Chemistry, CSIR-Indian Institute of Chemical Technology, Hyderabad 500007, India;1. School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, PR China;2. Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, PR China |
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| Abstract: | Compound 1 (IC50 = 35.2 ± 7.2 μM), a moderate FXR antagonist was discovered via high-throughput screening. Structure–activity relationship studies indicated that the shape and the lipophilicity of the substituents of the aromatic ring affect the activity dramatically, increasing the shape and the lipophilicity of the substituents of the aromatic ring enhances the potency of FXR antagonists. Especially, when the OH at C2 position of the aromatic ring was replaced by the OBn substituent (analog 2b), its activity could be improved to IC50 = 1.1 ± 0.1 μM. Besides, the length of the linker and the tetrazole structure are essential for retaining the activity. |
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| Keywords: | FXR antagonist SAR study Hydroxyacetophenone derivatives Non-steroidal |
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