Synthesis and evaluation of 8-amino-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one derivatives as glycogen synthase kinase-3 (GSK-3) inhibitors

• Published in: Bioorganic & medicinal chemistry letters 2013-07, Vol.23 (13), p.3983-3987
• Main Authors: Chun, Kwangwoo, Park, Ji-Seon, Lee, Han-Chang, Kim, Young-Ha, Ye, In-Hea, Kim, Kang-Jeon, Ku, Il-Whea, Noh, Min-Young, Cho, Goang-Won, Kim, Heejaung, Kim, Seung Hyun, Kim, Jeongmin
• Format: Article
• Language: English
• Subjects: 8-Amino-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one derivatives; Brain; Dose-Response Relationship, Drug; Drug Design; glycogen (starch) synthase; Glycogen Synthase Kinase 3 - antagonists & inhibitors; Glycogen Synthase Kinase 3 - metabolism; Glycogen synthase kinase-3; GSK-3 inhibitor; Humans; Models, Molecular; Molecular Structure; Protein Kinase Inhibitors - chemical synthesis; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; Pyridones - chemical synthesis; Pyridones - chemistry; Pyridones - pharmacology; Recombinant Proteins - metabolism; Structure-Activity Relationship; Triazoles - chemical synthesis; Triazoles - chemistry; Triazoles - pharmacology; water solubility
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2013.03.119

8-Amino-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one derivatives as novel glycogen synthase kinase-3 (GSK-3) inhibitors were reported. New potent glycogen synthase kinase-3 (GSK-3) inhibitors, 8-amino-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one derivatives, were designed by modeling, synthesized and evaluated in vitro. Compound 17c showed good potency in enzyme and cell-based assays (IC50=111nM, EC50=1.78μM). Moreover, it has demonstrated desirable water solubility, PK profile, and moderate brain penetration.