10.1021/acs.jmedchem.7b00922.s001 Allan S. Wagman Allan S. Wagman Rustum S. Boyce Rustum S. Boyce Sean P. Brown Sean P. Brown Eric Fang Eric Fang Dane Goff Dane Goff Johanna M. Jansen Johanna M. Jansen Vincent P. Le Vincent P. Le Barry H. Levine Barry H. Levine Simon C. Ng Simon C. Ng Zhi-Jie Ni Zhi-Jie Ni John M. Nuss John M. Nuss Keith B. Pfister Keith B. Pfister Savithri Ramurthy Savithri Ramurthy Paul A. Renhowe Paul A. Renhowe David B. Ring David B. Ring Wei Shu Wei Shu Sharadha Subramanian Sharadha Subramanian Xiaohui A. Zhou Xiaohui A. Zhou Cynthia M. Shafer Cynthia M. Shafer Stephen D. Harrison Stephen D. Harrison Kirk W. Johnson Kirk W. Johnson Dirksen E. Bussiere Dirksen E. Bussiere Synthesis, Binding Mode, and Antihyperglycemic Activity of Potent and Selective (5-Imidazol-2-yl-4-phenylpyrimidin-2-yl)[2-(2-pyridylamino)ethyl]amine Inhibitors of Glycogen Synthase Kinase 3 American Chemical Society 2017 Antihyperglycemic Activity Glycogen Synthase Kinase 3 analogue GSK 3 IC 50 rat hepatocytes Binding Mode aminopyridine moieties C -2 position convergently access insulin levels CHIR -611 type 2 diabetes -2-yl nanomolar range Compound 1 glycogen synthase 60 min insulin receptor-expressing CHO-IR cells insulin-stimulated glucose transport compounds 1 glucose disposal CT substitution patterns variety antidiabetic agents novel family glycogen synthase kinase 3 phenyl groups rodent models 2017-10-10 14:34:17 Dataset https://acs.figshare.com/articles/dataset/Synthesis_Binding_Mode_and_Antihyperglycemic_Activity_of_Potent_and_Selective_5-Imidazol-2-yl-4-phenylpyrimidin-2-yl_2-_2-pyridylamino_ethyl_amine_Inhibitors_of_Glycogen_Synthase_Kinase_3/5484787 In an effort to identify new antidiabetic agents, we have discovered a novel family of (5-imidazol-2-yl-4-phenylpyrimidin-2-yl)­[2-(2-pyridylamino)­ethyl]­amine analogues which are inhibitors of human glycogen synthase kinase 3 (GSK3). We developed efficient synthetic routes to explore a wide variety of substitution patterns and convergently access a diverse array of analogues. Compound <b>1</b> (CHIR-911, CT-99021, or CHIR-73911) emerged from an exploration of heterocycles at the C-5 position, phenyl groups at C-4, and a variety of differently substituted linker and aminopyridine moieties attached at the C-2 position. These compounds exhibited GSK3 IC<sub>50</sub>s in the low nanomolar range and excellent selectivity. They activate glycogen synthase in insulin receptor-expressing CHO-IR cells and primary rat hepatocytes. Evaluation of lead compounds <b>1</b> and <b>2</b> (CHIR-611 or CT-98014) in rodent models of type 2 diabetes revealed that single oral doses lowered hyperglycemia within 60 min, enhanced insulin-stimulated glucose transport, and improved glucose disposal without increasing insulin levels.