Discovery, Optimization, and Biological Evaluation of Sulfonamidoacetamides as an Inducer of Axon Regeneration

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• 作者：Jin-Mo Ku ; Kyuhee Park ; Jung Hun Lee ; Kyong Jin Cho ; Yeon-Ju Nam ; Dae-Youn Jeong ; Yu-Han Kim ; SoonJung Kwon ; Ju-Young Park ; Jungeun Yang ; Tae-gyu Nam ; Sung-Hwa Yoon ; Sangmee Ahn ; Yongmun Choi
• 刊名：Journal of Medicinal Chemistry
• 出版年：2016
• 出版时间：May 26, 2016
• 年：2016
• 卷：59
• 期：10
• 页码：4676-4687
• 全文大小：554K
• 年卷期：0
• ISSN：1520-4804

文摘

Axon regeneration after injury in the central nervous system is hampered in part because if an age-dependent decline in the intrinsic axon growth potential, and one of the strategies to stimulate axon growth in injured neurons involves pharmacological manipulation of implicated signaling pathways. Here we report phenotypic cell-based screen of chemical libraries and structure–activity-guided optimization that resulted in the identification of compound 7p which promotes neurite outgrowth of cultured primary neurons derived from the hippocampus, cerebral cortex, and retina. In an animal model of optic nerve injury, compound 7p was shown to induce growth of GAP-43 positive axons, indicating that the in vitro neurite outgrowth activity of compound 7p translates into stimulation of axon regeneration in vivo. Further optimization of compound 7p and elucidation of the mechanisms by which it elicits axon regeneration in vivo will provide a rational basis for future efforts to enhance treatment strategies.