Design, synthesis, and structure-activity relationship of substrate competitive, selective, and in vivo active triazole and thiadiazole inhibitors of the c-Jun N-terminal kinase.
We report comprehensive structure-activity relationship studies on a novel series of c-Jun N-terminal kinase (JNK) inhibitors. The compounds are substrate competitive inhibitors that bind to the docking site of the kinase. The reported medicinal chemistry and structure-based optimizations studies resulted in the discovery of selective and potent thiadiazole JNK inhibitors that display promising in vivo activity in mouse models of insulin insensitivity.
De
Surya K
SK
Infectious and Inflammatory Disease Center and Cancer Center, Burnham Institute for Medical Research, La Jolla, California 92037, USA.
Stebbins
John L
JL
Chen
Li-Hsing
LH
Riel-Mehan
Megan
M
Machleidt
Thomas
T
Dahl
Russell
R
Yuan
Hongbin
H
Emdadi
Aras
A
Barile
Elisa
E
Chen
Vida
V
Murphy
Ria
R
Pellecchia
Maurizio
M
D051698:Activating Transcription Factor 2 / Q000378:metabolism; D000818:Animals; D001665:Binding Sites; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D015195:Drug Design; D006367:HeLa Cells; D006801:Humans; D007004:Hypoglycemic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007333:Insulin Resistance; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008297:Male; D051379:Mice; D010766:Phosphorylation; D011485:Protein Binding; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D013830:Thiadiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013844:Thiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014230:Triazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
C540182:5-(5-nitrothiazol-2-ylthio)-1,3,4-thiadiazol-2-amine; C497105:ATF2 protein, human; D051698:Activating Transcription Factor 2; D007004:Hypoglycemic Agents; D013830:Thiadiazoles; D013844:Thiazoles; D014230:Triazoles; D048031:JNK Mitogen-Activated Protein Kinases