Highly selective c-Jun N-terminal kinase (JNK) 2 and 3 inhibitors with in vitro CNS-like pharmacokinetic properties prevent neurodegeneration |
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Authors: | Probst Gary D Bowers Simeon Sealy Jennifer M Truong Anh P Hom Roy K Galemmo Robert A Konradi Andrei W Sham Hing L Quincy David A Pan Hu Yao Nanhua Lin May Tóth Gergley Artis Dean R Zmolek Wes Wong Karina Qin Ann Lorentzen Colin Nakamura David F Quinn Kevin P Sauer John-Michael Powell Kyle Ruslim Lany Wright Sarah Chereau David Ren Zhao Anderson John P Bard Frédérique Yednock Ted A Griswold-Prenner Irene |
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Affiliation: | a Department of Medicinal Chemistry, Elan Pharmaceuticals, 180 Oyster Point Boulevard, South San Francisco, CA 94080, United States b Department of Process and Analytical Chemistry, Elan Pharmaceuticals, 180 Oyster Point Boulevard, South San Francisco, CA 94080, United States c Department of Molecular Design, Elan Pharmaceuticals, 180 Oyster Point 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 |
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Abstract: | In this Letter, we describe the discovery of selective JNK2 and JNK3 inhibitors, such as 10, that routinely exhibit >10-fold selectivity over JNK1 and >1000-fold selectivity over related MAPKs, p38α and ERK2. Substitution of the naphthalene ring affords an isoform selective JNK3 inhibitor, 30, with approximately 10-fold selectivity over both JNK1 and JNK2. A naphthalene ring penetrates deep into the selectivity pocket accounting for the differentiation amongst the kinases. Interestingly, the gatekeeper Met146 sulfide interacts with the naphthalene ring in a sulfur-π stacking interaction. Compound 38 ameliorates neurotoxicity induced by amyloid-β in human cortical neurons. Lastly, we demonstrate how to install propitious in vitro CNS-like properties into these selective inhibitors. |
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Keywords: | JNK inhibitor Selective Kinase |
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