title: Design, synthesis and biological evaluation of benzothiazepinones (BTZs) as novel non-ATP competitive inhibitors of glycogen synthase kinase-3β (GSK-3β).
abstract: Glycogen synthase kinase-3β (GSK-3β) plays a key role in type II diabetes and Alzheimer's diseases, to which non-ATP competitive inhibitors represent an effectively therapeutical approach due to their good specificity. Herein, a series of small molecules benzothiazepinones (BTZs) as novel non-ATP competitive inhibitors of GSK-3β have been designed and synthesized. The in vitro evaluation performed by luminescent assay showed most BTZ derivatives have inhibitory effects in micromolar scale. Among them compounds 6l, 6t and 6v have the IC50 values of 25.0 μM, 27.8 μM and 23.0 μM, respectively. Moreover 6v is devoid of any inhibitory activity in the assays to other thirteen protein kinases. Besides, SAR is analyzed and a hypothetical enzymatic binding mode is proposed by molecular docking study, which would be useful for new candidates design.
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Fudan University, 826 Zhangheng Rd, Shanghai 201203, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Zhang
authors.forename: Hai-Rong
authors.initials: HR
authors.lastname: Hu
authors.forename: Shi-Hui
authors.initials: SH
authors.lastname: Bian
authors.forename: Zhao-Hui
authors.initials: ZH
authors.lastname: Huang
authors.forename: Yong
authors.initials: Y
authors.lastname: Chu
authors.forename: De-Yong
authors.initials: DY
authors.lastname: Ye
mesh_terms: D001552:Benzazepines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001667:Binding, Competitive / Q000187:drug effects; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D001552:Benzazepines; D047428:Protein Kinase Inhibitors; D011994:Recombinant Proteins; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3