Acta Pharmacologica Sinica 2007 December; 28 (12): 2040-2052; doi: 10.1111/j.1745-7254.2007.00670.x

Acta Pharmacologica Sinica 2007 December; 28 (12): 2040-2052; doi: 10.1111/j.1745-7254.2007.00670.x

Original Article

Structure-based drug design of a novel family of chalcones as PPARα agonists: virtual screening, synthesis, and biological activities in vitro¹

Xiang-hua LI^2,3, Han-jun ZOU^2,3, An-hui WU², Yang-liang YE², Jian-hua SHEN^2,4

²Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China

Aim: design and synthesize a novel class of peroxisome proliferator-activated receptors (PPAR)α agonists, which is obtained by the combination of the classical fibrate "head group", a linker with appropriate length and a chalcone.

Methods: Thirty seven compounds were designed and identified employing the virtual screening approach. Six compounds were then selected for synthesis and bioassay according to the virtual screening results, structural similarity, and synthetic complexity.

Results: Six new compounds (4b and 4d-h) were synthesized and bioassayed. All were found to be potent PPARα agonists, compound 4 h being the most prominent with a 50% effective concentration value of 0.06 µmol/L.

Conclusion: This study provides a promising novel family of chalcones with a potential hypolipidemic effect.

Keywords: peroxisome proliferator-activated receptors; drug design; virtual screening

¹Project supported by grants from the Na-tional Natural Science Foundation of China (No 30623008) and the Dengshan Project from the Shanghai Science and Technology Commission (No 064319015).

³These authors contributed equally to this work.
⁴Correspondence to Prof Jian-hua SHEN.
Phn/Fax 86-21-5080-7188.
E-mail jhshen@mail.shcnc.ac.cn
Received 2007-04-26 Accepted 2007-06-19

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