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Design and synthesis of a novel, orally active, brain penetrant, tri-substituted thiophene based JNK inhibitor |
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| Authors: | Bowers Simeon Truong Anh P Neitz R Jeffrey Neitzel Martin Probst Gary D Hom Roy K Peterson Brian Galemmo Robert A Konradi Andrei W Sham Hing L Tóth Gergley Pan Hu Yao Nanhua Artis Dean R Brigham Elizabeth F Quinn Kevin P Sauer John-Michael Powell Kyle Ruslim Lany Ren Zhao Bard Frédérique Yednock Ted A Griswold-Prenner Irene |
| Affiliation: | a Department of Chemical Sciences, Elan Pharmaceuticals, 180 Oyster Point Boulevard, South San Francisco, CA 94080, United States b Department of Molecular Design, Elan Pharmaceuticals, 180 Oyster Point Boulevard, South San Francisco, CA 94080, United States c Department of Pharmacology, Elan Pharmaceuticals, 800 Gateway Boulevard, South San Francisco, CA 94080, United States d Department of Lead Finding, Drug Disposition, and Safety Evaluation, Elan Pharmaceuticals, 800 Gateway Boulevard, South San Francisco, CA 94080, United States e Department of Biology, Elan Pharmaceuticals, 1000 Gateway Boulevard, South San Francisco, CA 94080, United States |
| Abstract: | The SAR of a series of tri-substituted thiophene JNK3 inhibitors is described. By optimizing both the N-aryl acetamide region of the inhibitor and the 4-position of the thiophene we obtained single digit nanomolar compounds, such as 47, which demonstrated an in vivo effect on JNK activity when dosed orally in our kainic acid mouse model as measured by phospho-c-jun reduction. |
| Keywords: | c-Jun N-terminal kinases JNK inhibitor Neurodegeneration Phospho-c-jun reduction |
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