磺胺
化学
激酶
噻吩
药理学
结构-活动关系
程序性细胞死亡
生物活性
c-jun公司
彪马
苯并三唑
细胞凋亡
立体化学
生物化学
体外
转录因子
医学
基因
有机化学
作者
Thomas Rückle,Marco A. Biamonte,Tania Grippi-Vallotton,Steve Arkinstall,Yves Cambet,Montserrat Camps,Christian Chabert,Dennis J. Church,S. Halazy,Xuliang Jiang,Isabelle Martinou,Anthony Nichols,Wolfgang Sauer,Jean‐Pierre Gotteland
摘要
Several lines of evidence support the hypothesis that c-Jun N-terminal kinases (JNKs) play a critical role in a wide range of disease states including cell death (apoptosis)-related and inflammatory disorders (epilepsy, brain, heart and renal ischemia, neurodegenerative diseases, multiple sclerosis, rheumatoid arthritis, and inflammatory bowel syndrome). The screening of a compound collection led to the identification of a 2-(benzoylaminomethyl)thiophene sulfonamide (AS004509, compound I) as a potent and selective JNK inhibitor. Chemistry and structure−activity relationship (SAR) studies performed around this novel kinase-inhibiting motif indicated that the left and central parts of the molecule were instrumental to maintaining potency at the enzyme. Accordingly, we investigated the JNK-inhibiting properties of a number of variants of the right-hand moiety of the molecule, which led to the identification of 2-(benzoylaminomethyl)thiophene sulfonamide benzotriazole (AS600292, compound 50a), the first potent and selective JNK inhibitor of this class which demonstrates a protective action against neuronal cell death induced by growth factor and serum deprivation.
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