Discovery of N-hydroxy-3-alkoxybenzamides as direct acid sphingomyelinase inhibitors using a ligand-based pharmacophore model

作者：Yang, Kan; Nong, Keyi; Gu, Qinlan; Dong, Jibin^*; Wang, Jinxin^*

来源：European Journal of Medicinal Chemistry, 2018, 151: 389-400.

DOI：10.1016/j.ejmech.2018.03.065

• Acid sphingomyelinase
• Inhibitors
• Pharmacophore model
• Anti-apoptosis
• Anti-inflammatory

Acid sphingomyelinase (ASM) has been shown to be involved in many physiological processes, emerging to be a promising drug target. In this study, we constructed a ligand-based pharmacophore model of ASM inhibitors and applied this model to optimize the lead compound alpha-mangostin, a known inhibitor of ASM. 23 compounds were designed and evaluated in vitro for ASM inhibition, of these, 10 compounds were found to be more potent than alpha-mangostin. This high hit ratio confirmed that the presented model is very effective and practical. The most potent hit, 1c, was found to selectively and competitively inhibit the enzyme and inhibit the generation of ceramide in a dose-dependent manner. Furthermore, 1c showed favorable anti-apoptosis and anti-inflammatory activity. Interactions with key residues and the Zn2+ cofactor of 1c were found by docking simulation. These results provide promising leads and important guidance for further development of efficient ASM inhibitors and drug candidates.

• 出版日期2018-5-10
• 单位中国药科大学; 复旦大学