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

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

  • Bioorg Med Chem Lett. 2010 Nov 15;20(22):6696-8. doi: 10.1016/j.bmcl.2010.09.005.
Shigehiro Asano 1,  Masafumi Komiya,  Nobuyuki Koike,  Erina Koga,  Shogo Nakatani,  Yoshiaki Isobe
Affiliations

Affiliation

  • 1 Research Division, Dainippon Sumitomo Pharma Co., Ltd, 3-1-98 Kasugade Naka, Konohana-ku, Osaka 554-0022, Japan. [email protected]
PMID: 20875738 DOI: 10.1016/j.bmcl.2010.09.005
Abstract

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.

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