Abstract
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.
Publication types
-
Research Support, N.I.H., Extramural
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Activating Transcription Factor 2 / metabolism
-
Animals
-
Binding Sites
-
Diabetes Mellitus, Type 2 / drug therapy
-
Drug Design
-
HeLa Cells
-
Humans
-
Hypoglycemic Agents / chemical synthesis*
-
Hypoglycemic Agents / chemistry
-
Hypoglycemic Agents / pharmacology
-
Insulin Resistance
-
JNK Mitogen-Activated Protein Kinases / antagonists & inhibitors*
-
JNK Mitogen-Activated Protein Kinases / metabolism
-
Male
-
Mice
-
Phosphorylation
-
Protein Binding
-
Structure-Activity Relationship
-
Substrate Specificity
-
Thiadiazoles / chemical synthesis*
-
Thiadiazoles / chemistry
-
Thiadiazoles / pharmacology
-
Thiazoles / chemical synthesis*
-
Thiazoles / chemistry
-
Thiazoles / pharmacology
-
Triazoles / chemical synthesis*
-
Triazoles / chemistry
-
Triazoles / pharmacology
Substances
-
5-(5-nitrothiazol-2-ylthio)-1,3,4-thiadiazol-2-amine
-
ATF2 protein, human
-
Activating Transcription Factor 2
-
Hypoglycemic Agents
-
Thiadiazoles
-
Thiazoles
-
Triazoles
-
JNK Mitogen-Activated Protein Kinases