Design and synthesis of a novel, orally active, brain penetrant, tri-substituted thiophene based JNK inhibitor

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• 作者：Simeon Bowers^a ; ^{simeon.bowers@elan.com} ; Anh P. Truong^a ; ^{anh.truong@elan.com} ; R. Jeffrey Neitz^a ; Martin Neitzel^a ; Gary D. Probst^a ; Roy K. Hom^a ; Brian Peterson^a ; Robert A. Galemmo Jr.^a ; Andrei W. Konradi^a ; Hing L. Sham^a ; Gergley Tó ; th^b ; Hu Pan^b ; Nanhua Yao^b ; Dean R. Artis^b ; Elizabeth F. Brigham^c ; Kevin P. Quinn^d ; John-Michael Sauer^d ; Kyle Powell^e ; Lany Ruslim^e ; Zhao Ren^e ; Fré ; dé ; rique Bard^e ; Ted A. Yednock^a ; ^b ; ^c ; ^d ; ^e ; Irene Griswold-Prenner^e
• 关键词：c-Jun N-terminal kinases ; JNK inhibitor ; Neurodegeneration ; Phospho-c-jun reduction
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2011
• 出版时间：15 March 2011
• 年：2011
• 卷：21
• 期：6
• 页码：1838-1843
• 全文大小：1308 K

文摘

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.