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.