Lipid accumulation inhibitory activities of novel isoxazole-based chenodeoxycholic acids: Design, synthesis and preliminary mechanism study. Issue 17 (15th September 2018)

• Record Type: Journal Article
• Authors: Qiu, Rongmao; Luo, Guoshun; Li, Xinyu; Zheng, Fan; Li, Haolin; Zhang, Jin; You, Qidong; Xiang, Hua
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 28:Issue 17(2018)
• Page Start: 2879
• Page End: 2884
• Publication Date: 2018-09-15
• Subjects: Hyperlipidemia -- Hybrids -- FXR -- SREBP-1c -- 3T3-L1 adipocytes; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2018.07.026
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Highlights: A series of isoxazole-chenodeoxycholic acid hybrids have been designed and synthesized. The most active compound 16b reduced the lipid accumulation up to 30.5%. 16b blocked lipid accumulation via activating FXR-SHP-SREBP-1c signaling pathway. 16b fitted well in the binding pocket of FXR and displayed satisfied physical property. Abstract: In continuation of our drug discovery program on hyperlipidemia, a series of novel isoxazole-chenodeoxycholic acid hybrids were designed, synthesized and evaluated for their lipid-lowering effects. Preliminary screening of all the synthesized compounds was done by using a 3T3-L1 adipocyte model, in which the most active compound 16b could significantly reduce the lipid accumulation up to 30.5% at a nontoxic concentration 10 μM. Further mechanism studies revealed that 16b blocked lipid accumulation via activating FXR-SHP signaling pathway, efficiently down-regulated the expression of key lipogenesis regulator SREBP-1c.