Synthesis and structure-activity relationship of 4-quinolone-3-carboxylic acid based inhibitors of glycogen synthase kinase-3β

Oana M Cociorva; Bei Li; Tyzoon Nomanbhoy; Qiang Li; Ayako Nakamura; Kai Nakamura; Masahiro Nomura; Kyoko Okada; Shigeki Seto; Kazuhiro Yumoto; Marek Liyanage; Melissa C Zhang; Arwin Aban; Brandon Leen; Anna Katrin Szardenings; Jonathan S Rosenblum; John W Kozarich; Yasushi Kohno; Kevin R Shreder

doi:10.1016/j.bmcl.2011.07.073

Synthesis and structure-activity relationship of 4-quinolone-3-carboxylic acid based inhibitors of glycogen synthase kinase-3β

Bioorg Med Chem Lett. 2011 Oct 1;21(19):5948-51. doi: 10.1016/j.bmcl.2011.07.073. Epub 2011 Aug 5.

Affiliation

¹ ActivX Biosciences, Inc., 11025 N. Torrey Pines Road, La Jolla, CA 92037, USA.

PMID: 21873061
DOI: 10.1016/j.bmcl.2011.07.073

Abstract

The synthesis, GSK-3β inhibitory activity, and anti-microbial activity of bicyclic and tricyclic derivatives of the 5,7-diamino-6-fluoro-4-quinolone-3-carboxylic acid scaffold were studied. Kinase selectivity profiling indicated that members of this class were potent and highly selective GSK-3 inhibitors.

MeSH terms

4-Quinolones / chemistry
Anti-Bacterial Agents / chemical synthesis
Anti-Bacterial Agents / chemistry
Anti-Bacterial Agents / pharmacology
Clinical Trials as Topic
Drug Design
Drug Evaluation, Preclinical
Glycogen Synthase Kinase 3 / antagonists & inhibitors*
Glycogen Synthase Kinase 3 / metabolism
Glycogen Synthase Kinase 3 beta
HL-60 Cells
High-Throughput Screening Assays
Humans
Inhibitory Concentration 50
Isoenzymes
Molecular Targeted Therapy
Protein Kinase Inhibitors / chemical synthesis*
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Structure-Activity Relationship
Substrate Specificity

Substances

4-Quinolones
Anti-Bacterial Agents
Isoenzymes
Protein Kinase Inhibitors
GSK3B protein, human
Glycogen Synthase Kinase 3 beta
Glycogen Synthase Kinase 3