Synthesis,biological evaluation and SAR studies of ursolic acid 3β-ester derivatives as novel CETP inhibitors |
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| Institution: | 1. Department of Medicinal Chemistry, School of Pharmacy, Nanjing Medical University, Nanjing 211166, China;2. State Key Laboratory of Natural Medicines and Center of Drug Discovery, China Pharmaceutical University, Nanjing 210009, China;3. Key Lab of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing 211166, China;4. Department of Cardiology, First People’s Hospital of Yancheng, Fourth Affiliated Hospital of Nantong University, Yancheng 224005, China;1. Molecular Imaging and Neuropathology Division, New York State Psychiatric Institute, New York, USA;2. Department of Psychiatry, Columbia University Medical Center, New York, USA;3. Department of Radiology, Wake Forest School of Medicine, Winston Salem, North Carolina, USA;4. Department of Radiology, Columbia University Medical Center, New York, USA;1. Department of Pharmaceutical Chemistry, University of Kansas, Lawrence, KS 66047, United States;2. Department of Medicinal Chemistry, University of Kansas, Lawrence, KS 66047, United States;1. Drug Delivery Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Australia;2. Department of Veterinary Sciences, The University of Melbourne, Werribee, Australia;3. Pfizer Global Research and Development, Groton, CT, USA;1. Guizhou University, Guiyang, Guizhou, China;2. Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academy of Sciences, 202 South Sha-chong Road, Guiyang, Guizhou, China |
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| Abstract: | Cholesteryl ester transfer protein (CETP) is an attractive therapeutic target for the prevention and treatment of cardiovascular diseases by lowering low-density lipoprotein cholesterol levels as well as raising high-density lipoprotein cholesterol levels in human plasma. Herein, a series of ursolic acid 3β-ester derivatives were designed, synthesized and evaluated for the CETP inhibiting activities. Among these compounds, the most active compound is U12 with an IC50 value of 2.4 μM in enzymatic assay. The docking studies showed that the possible hydrogen bond interactions between the carboxyl groups at both ends of the molecule skeleton and several polar residues (such as Ser191, Cys13 and Ser230) in the active site region of CETP could significantly enhance the inhibition activity. This study provides structural insight of the interactions between these pentacyclic triterpenoid 3β-ester derivatives and CETP protein for the further modification and optimization. |
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| Keywords: | Cardiovascular diseases CETP inhibitor Pentacyclic triterpenes Usolic acid Molecular docking |
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