Pharmacophore-based design, synthesis, and biological evaluation of novel 3-((3,4-dichlorophenyl)(4-substituted benzyl)amino) propanamides as cholesteryl ester transfer protein (CETP) inhibitors

Cholesteryl ester transfer protein (CETP) is a plasma glycoprotein that plays an important role in decreasing high-density lipoprotein cholesterol (HDL-C) levels and increasing low-density lipoprotein cholesterol (LDL-C) levels. Inhibition of CETP may be a new therapy for treating atherosclerosis. Herein, we report the development of a ligand-based pharmacophore model and pharmacophore-based virtual screening of the ZINC/big-n-greasy database, leading to the identification of compound H-10 as a potential CETP inhibitor in vitro. Based on H-10, a series of 3-((3,4-dichlorophenyl)(4-substituted benzyl)amino) propanamides were designed, synthesized, and evaluated against CETP. Compound 4l was found to have the best activity, resulting in 85.0% inhibition of CETP at 10 μmol/L.

Graphical abstractA ligand-based pharmacophore with 5 features was developed and used to database screening. A novel series of 3-((3,4-dichlorophenyl)(4-substituted benzyl)amino) propanamides were designed based on H-10 which is a potential CETP inhibitor obtained by pharmacophore-based database screening. Compound 4l was found to be a preferable CETP inhibitor with inhibition rate of 85.0%.Figure optionsDownload full-size imageDownload as PowerPoint slide