Design,synthesis and biological evaluation of N,N-3-phenyl-3-benzylaminopropanamide derivatives as novel cholesteryl ester transfer protein inhibitor |
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| Affiliation: | 1. Laboratory of Growth Regulators, Centre of the Region Haná for Biotechnological and Agricultural Research, Institute of Experimental Botany ASCR & Palacky´ University, Šlechtitelu° 27, 783 71 Olomouc, Czech Republic;2. Organic Research Laboratory, Department of Bioresources and Food Sciences, College of Life and Environmental Sciences, Konkuk University, Seoul, Republic of Korea;3. Department of Chemistry, J.N.T. University, Kukatpally, Hyderabad 500 085, India;4. Regional Centre of Advanced Technologies and Materials, Department of Physical Chemistry, Faculty of Science, Palacky University, Šlechtitelů 11, Olomouc, Czech Republic;5. Department of Life Science, Dongguk University, Goyang, Gyeonggi-do 10326, Republic of Korea;6. Department of Food Science and Biotechnology, Dongguk University, Biomedical Campus, 32 Dongguk-ro, Ilsandong-gu, Goyang-si, Gyenggi-do, Republic of Korea |
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| Abstract: | A series of N,N-3-phenyl-3-benzylaminopropanamide derivatives were identified as novel CETP (cholesteryl ester transfer protein) inhibitors. In our previous study, lead compound L10 was discovered by pharmacophore-based virtual screening (Dong-Mei Zhao et al., 2014). Based on L10 (IC50 8.06 μM), compound HL6 (IC50 10.7 μM) was discovered following systematic structure variation and biological tests. Further optimization of the structure–activity relationship (SAR) resulted in N,N-3-phenyl-3-benzylaminopro panamides derivatives as novel CETP inhibitors. They were synthesized and evaluated against CETP by BODIPY-CE fluorescence assay. Among them, HL16 (IC50 0.69 μM) was a highly potent CETP inhibitor in vitro. In addition, HL16 exhibited favorable HDL-C enhancement and LDL-C reduction in vivo by hamster. The molecular docking of HL16 into the CETP was performed. The binding mode demonstrated that HL16 occupied the CETP binding site and formed interactions with the key amino acid residues. |
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| Keywords: | CETP inhibitor Molecular docking |
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