4-Acylamino-6-arylfuro[2,3-d]pyrimidines: potent and selective glycogen synthase kinase-3 inhibitors

Yutaka Maeda; Masato Nakano; Hideyuki Sato; Yasushi Miyazaki; Stephanie L Schweiker; Jeffery L Smith; Anne T Truesdale

doi:10.1016/j.bmcl.2004.05.064

4-Acylamino-6-arylfuro[2,3-d]pyrimidines: potent and selective glycogen synthase kinase-3 inhibitors

Bioorg Med Chem Lett. 2004 Aug 2;14(15):3907-11. doi: 10.1016/j.bmcl.2004.05.064.

Authors

Yutaka Maeda¹, Masato Nakano, Hideyuki Sato, Yasushi Miyazaki, Stephanie L Schweiker, Jeffery L Smith, Anne T Truesdale

Affiliation

¹ Chemistry Department, Tsukuba Research Laboratories, GlaxoSmithKline K.K., Wadai 43, Tsukuba, Ibaraki 300-4247, Japan.

PMID: 15225695
DOI: 10.1016/j.bmcl.2004.05.064

Abstract

Modeling studies of a furo[2,3-d]pyrimidine GSK-3 hit compound 1 superimposed onto the X-ray crystal structure of a legacy pyrazolo[3,4-c]pyridazine GSK-3 inhibitor 2 led to the identification of 4-acylamino-6-arylfuro[2,3-d]pyrimidine template 3. Synthesis of analogues based on template 3 has resulted in a number of potent and selective GSK-3beta inhibitors. The most potent and selective compound was the m-pyridyl analogue 24.

MeSH terms

Binding Sites
Enzyme Inhibitors / chemical synthesis*
Enzyme Inhibitors / pharmacology*
Glycogen Synthase Kinase 3 / antagonists & inhibitors*
Glycogen Synthase Kinase 3 / chemistry
Kinetics
Models, Molecular
Pyrimidines / chemical synthesis*
Pyrimidines / pharmacology*
Structure-Activity Relationship
Vascular Endothelial Growth Factor Receptor-2 / antagonists & inhibitors

Substances

Enzyme Inhibitors
Pyrimidines
Vascular Endothelial Growth Factor Receptor-2
Glycogen Synthase Kinase 3