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Synthesis and optimization of thiadiazole derivatives as a novel class of substrate competitive c-Jun N-terminal kinase inhibitors.

ABSTRACT: A series of thiadiazole derivatives has been designed as potential allosteric, substrate competitive inhibitors of the protein kinase JNK. We report on the synthesis, characterization and evaluation of a series of compounds that resulted in the identification of potent and selective JNK inhibitors targeting its JIP-1 docking site.

SUBMITTER: De SK

PROVIDER: S-EPMC2818674 | biostudies-literature | 2010 Jan

REPOSITORIES: biostudies-literature

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Synthesis and optimization of thiadiazole derivatives as a novel class of substrate competitive c-Jun N-terminal kinase inhibitors.

De Surya K SK Chen Vida V Stebbins John L JL Chen Li-Hsing LH Cellitti Jason F JF Machleidt Thomas T Barile Elisa E Riel-Mehan Megan M Dahl Russell R Yang Li L Emdadi Aras A Murphy Ria R Pellecchia Maurizio M

Bioorganic & medicinal chemistry 20091211 2

A series of thiadiazole derivatives has been designed as potential allosteric, substrate competitive inhibitors of the protein kinase JNK. We report on the synthesis, characterization and evaluation of a series of compounds that resulted in the identification of potent and selective JNK inhibitors targeting its JIP-1 docking site. ...[more]

PMID: 20045647

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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.

Project description: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.

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