6B8J

Co-structure of human glycogen synthase kinase beta with a selective (5-imidazol-2-yl-4-phenylpyrimidin-2-yl)[2-(2-pyridylamino)ethyl]amine inhibitor

Summary for 6B8J

• Entry DOI: 10.2210/pdb6b8j/pdb
• Descriptor: Glycogen synthase kinase-3 beta, VAL-SEP-ARG-ARG, GLYCEROL, ... (5 entities in total)
• Functional Keywords: kinase, transferase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (Human); More
• Cellular location: Cytoplasm : P49841
• Total number of polymer chains: 2
• Total formula weight: 48037.22

Authors

Bussiere, D.E. (deposition date: 2017-10-08, release date: 2017-11-08, Last modification date: 2024-11-20)

Primary citation

Wagman, A.S.,Boyce, R.S.,Brown, S.P.,Fang, E.,Goff, D.,Jansen, J.M.,Le, V.P.,Levine, B.H.,Ng, S.C.,Ni, Z.J.,Nuss, J.M.,Pfister, K.B.,Ramurthy, S.,Renhowe, P.A.,Ring, D.B.,Shu, W.,Subramanian, S.,Zhou, X.A.,Shafer, C.M.,Harrison, S.D.,Johnson, K.W.,Bussiere, D.E.
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.
J. Med. Chem., 60:8482-8514, 2017

PubMed Abstract: 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 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 ICs 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.

PubMed: 29016121
DOI: 10.1021/acs.jmedchem.7b00922

Experimental method

X-RAY DIFFRACTION (2.595 Å)