Discovery of a novel 2,3,11,11a-tetrahydro-1H-pyrazino[1,2-b]isoquinoline-1,4(6H)-dione series promoting neurogenesis of human neural progenitor cells

• Published in: Bioorganic & medicinal chemistry letters Vol. 25; no. 17; pp. 3748 - 3753
• Main Authors: Lin, Hong, Fang, Haiyan, Wang, Jamie, Meng, Qinghua, Dai, Xuedong, Wu, Sharon, Luo, Jie, Pu, Dan, Chen, Libo, Minick, Douglas, Arai, Ken, Mandeville, Emiri T., Lo, Eng, Holder, Julie C., Chuang, Tsu Tshen, Zhao, Jing
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 01.09.2015; Elsevier
• Subjects: Administration, Oral; Animals; Brain - drug effects; Cell Differentiation - drug effects; Cells, Cultured; Chemistry; Chemistry Techniques, Synthetic; Chemistry, Medicinal; Chemistry, Organic; Dose-Response Relationship, Drug; Drug Discovery; Drug Evaluation, Preclinical - methods; Half-Life; Humans; Isoquinolines - administration & dosage; Isoquinolines - chemistry; Isoquinolines - pharmacokinetics; Isoquinolines - pharmacology; Life Sciences & Biomedicine; Mice, Inbred C57BL; Neural progenitor cell; Neural Stem Cells - cytology; Neural Stem Cells - drug effects; Neurogenesis; Neurogenesis - drug effects; Pharmacology & Pharmacy; Physical Sciences; Pyrazines - administration & dosage; Pyrazines - chemistry; Pyrazines - pharmacokinetics; Science & Technology; Structure-Activity Relationship; Neurogenesis; Neural progenitor cell; Structure–activity relationship; MEMORY; Structure-activity relationship; ALZHEIMERS-DISEASE; DRUG DISCOVERY; HIPPOCAMPAL NEUROGENESIS; BRAIN; STRATEGIES; TOOL
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2015.05.084

[Display omitted] A novel neurogenic compound (1), discovered from a mouse neural progenitor cell (NPC) screen, showed profound neurogenic effect on human NPCs. Synthesis and SAR of this novel 2,3,11,11a-tetrahydro-1H-pyrazino[1,2-b]isoquinoline-1,4(6H)-dione series are described. Compound 20 is brain penetrable in rodents, and promotes neurogenesis in wild type mice, therefore it is a good tool molecule to study neurogenesis induction as a potential treatment for conditions associated with neurogenesis impairment diseases.