title: 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.
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.
authors.affiliation: Infectious and Inflammatory Disease Center and Cancer Center, Burnham Institute for Medical Research, La Jolla, California 92037, USA.
authors.forename: Surya K
authors.initials: SK
authors.lastname: De
authors.forename: John L
authors.initials: JL
authors.lastname: Stebbins
authors.forename: Li-Hsing
authors.initials: LH
authors.lastname: Chen
authors.forename: Megan
authors.initials: M
authors.lastname: Riel-Mehan
authors.forename: Thomas
authors.initials: T
authors.lastname: Machleidt
authors.forename: Russell
authors.initials: R
authors.lastname: Dahl
authors.forename: Hongbin
authors.initials: H
authors.lastname: Yuan
authors.forename: Aras
authors.initials: A
authors.lastname: Emdadi
authors.forename: Elisa
authors.initials: E
authors.lastname: Barile
authors.forename: Vida
authors.initials: V
authors.lastname: Chen
authors.forename: Ria
authors.initials: R
authors.lastname: Murphy
authors.forename: Maurizio
authors.initials: M
authors.lastname: Pellecchia
mesh_terms: 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
chemical_list: 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