5,6,7,8-Tetrahydropyrido[4,3-d]pyrimidines as novel class of potent and highly selective CaMKII inhibitors

A novel series of 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidines containing substituted phenyl sulfonamide are synthesized and evaluated for their inhibitory activity against CaMKII. Substituents on the phenyl group had significant impact on CaMKII inhibition, in particular, the inhibitory activity of 8...

Full description

Saved in:
Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2010-11, Vol.20 (22), p.6696-6698
Main Authors: Asano, Shigehiro, Komiya, Masafumi, Koike, Nobuyuki, Koga, Erina, Nakatani, Shogo, Isobe, Yoshiaki
Format: Article
Language:English
Subjects:
5,6,7,8-Tetrahydropyrido[4,3-d]pyrimidines
Analytical, structural and metabolic biochemistry
Biological and medical sciences
Calcium-Calmodulin-Dependent Protein Kinase Type 2 - antagonists & inhibitors
Calmodulin-dependent protein kinase II
Enzymes and enzyme inhibitors
Fundamental and applied biological sciences. Psychology
Inhibitors
Medical sciences
Miscellaneous
Pharmacology. Drug treatments
Protein Kinase Inhibitors - pharmacology
Pyrimidines - pharmacology
Transferases
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:A novel series of 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidines containing substituted phenyl sulfonamide are synthesized and evaluated for their inhibitory activity against CaMKII. Substituents on the phenyl group had significant impact on CaMKII inhibition, in particular, the inhibitory activity of 8p was 25-fold higher than that of KN-93, a known CaMKII inhibitor. Michaelis–Menten analysis of a representative compound suggested that the synthesized pyrimidines are calmodulin non-competitive inhibitors. Finally, 8p exhibited more than 100-fold higher selectivity for CaMKII over five types of off-target kinases.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2010.09.005