title: 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.
abstract: 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.
authors.affiliation: Regenerative Medicine Discovery Performance Unit, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, PA 19426, USA. Electronic address: hong.2.lin@gsk.com.
authors.forename: Hong
authors.initials: H
authors.lastname: Lin
authors.affiliation: Regenerative Medicine Discovery Performance Unit, GlaxoSmithKline, 898 Halei Road, Zhangjiang Hi-tech Park, Pudong, Shanghai 201203, PR China.
authors.forename: Haiyan
authors.initials: H
authors.lastname: Fang
authors.affiliation: Regenerative Medicine Discovery Performance Unit, GlaxoSmithKline, 898 Halei Road, Zhangjiang Hi-tech Park, Pudong, Shanghai 201203, PR China.
authors.forename: Jamie
authors.initials: J
authors.lastname: Wang
authors.affiliation: Regenerative Medicine Discovery Performance Unit, GlaxoSmithKline, 898 Halei Road, Zhangjiang Hi-tech Park, Pudong, Shanghai 201203, PR China.
authors.forename: Qinghua
authors.initials: Q
authors.lastname: Meng
authors.affiliation: Regenerative Medicine Discovery Performance Unit, GlaxoSmithKline, 898 Halei Road, Zhangjiang Hi-tech Park, Pudong, Shanghai 201203, PR China.
authors.forename: Xuedong
authors.initials: X
authors.lastname: Dai
authors.affiliation: Regenerative Medicine Discovery Performance Unit, GlaxoSmithKline, 898 Halei Road, Zhangjiang Hi-tech Park, Pudong, Shanghai 201203, PR China.
authors.forename: Sharon
authors.initials: S
authors.lastname: Wu
authors.affiliation: Regenerative Medicine Discovery Performance Unit, GlaxoSmithKline, 898 Halei Road, Zhangjiang Hi-tech Park, Pudong, Shanghai 201203, PR China.
authors.forename: Jie
authors.initials: J
authors.lastname: Luo
authors.affiliation: Platform Technology and Science, GlaxoSmithKline, 898 Halei Road, Zhangjiang Hi-tech Park, Pudong, Shanghai 201203, PR China.
authors.forename: Dan
authors.initials: D
authors.lastname: Pu
authors.affiliation: Platform Technology and Science, GlaxoSmithKline, 898 Halei Road, Zhangjiang Hi-tech Park, Pudong, Shanghai 201203, PR China.
authors.forename: Libo
authors.initials: L
authors.lastname: Chen
authors.affiliation: Platform Technology and Science, GlaxoSmithKline, 5 Moore Drive, RTP, NC 27709, USA.
authors.forename: Douglas
authors.initials: D
authors.lastname: Minick
authors.affiliation: Harvard Stem Cell Institute, Massachusetts General Hospital, Building 149, 13th Street, Charlestown, MA 02129, USA.
authors.forename: Ken
authors.initials: K
authors.lastname: Arai
authors.affiliation: Harvard Stem Cell Institute, Massachusetts General Hospital, Building 149, 13th Street, Charlestown, MA 02129, USA.
authors.forename: Emiri T
authors.initials: ET
authors.lastname: Mandeville
authors.affiliation: Harvard Stem Cell Institute, Massachusetts General Hospital, Building 149, 13th Street, Charlestown, MA 02129, USA.
authors.forename: Eng
authors.initials: E
authors.lastname: Lo
authors.affiliation: Regenerative Medicine Discovery Performance Unit, GlaxoSmithKline, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK.
authors.forename: Julie C
authors.initials: JC
authors.lastname: Holder
authors.affiliation: Regenerative Medicine Discovery Performance Unit, GlaxoSmithKline, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK.
authors.forename: Tsu Tshen
authors.initials: TT
authors.lastname: Chuang
authors.affiliation: Regenerative Medicine Discovery Performance Unit, GlaxoSmithKline, 898 Halei Road, Zhangjiang Hi-tech Park, Pudong, Shanghai 201203, PR China.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhao
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001921:Brain / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D060326:Chemistry Techniques, Synthetic; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D004353:Drug Evaluation, Preclinical / Q000379:methods; D006207:Half-Life; D006801:Humans; D007546:Isoquinolines / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D008810:Mice, Inbred C57BL; D058953:Neural Stem Cells / Q000166:cytology / Q000187:drug effects*; D055495:Neurogenesis / Q000187:drug effects*; D011719:Pyrazines / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D013329:Structure-Activity Relationship
chemical_list: C000607685:2,3,11,11a-tetrahydro-1H-pyrazino(1,2-b)isoquinoline-1,4(6H)-dione; D007546:Isoquinolines; D011719:Pyrazines
keywords: Neural progenitor cell; Neurogenesis; Structure–activity relationship