jm7b00922_si_001.csv (9.12 kB)
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
dataset
posted on 2017-10-10, 14:34 authored by Allan
S. Wagman, Rustum S. Boyce, Sean P. Brown, Eric Fang, Dane Goff, Johanna M. Jansen, Vincent P. Le, Barry H. Levine, Simon C. Ng, Zhi-Jie Ni, John M. Nuss, Keith B. Pfister, Savithri Ramurthy, Paul A. Renhowe, David B. Ring, Wei Shu, Sharadha Subramanian, Xiaohui A. Zhou, Cynthia M. Shafer, Stephen D. Harrison, Kirk W. Johnson, Dirksen E. BussiereIn 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 1 (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 IC50s 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 1 and 2 (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.
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Antihyperglycemic ActivityGlycogen Synthase Kinase 3analogueGSK 3 IC 50rat hepatocytesBinding Modeaminopyridine moietiesC -2 positionconvergently accessinsulin levelsCHIR -611type 2 diabetes-2-ylnanomolar rangeCompound 1glycogen synthase60 mininsulin receptor-expressing CHO-IR cellsinsulin-stimulated glucose transportcompounds 1glucose disposalCTsubstitution patternsvarietyantidiabetic agentsnovel familyglycogen synthase kinase 3phenyl groupsrodent models
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