Rückle Thomas, Biamonte Marco, Grippi-Vallotton Tania, Arkinstall Steve, Cambet Yves, Camps Montserrat, Chabert Christian, Church Dennis J, Halazy Serge, Jiang Xuliang, Martinou Isabelle, Nichols Anthony, Sauer Wolfgang, Gotteland Jean-Pierre
Serono Pharmaceutical Research Institute, 14 Chemin des Aulx, 1228 Plan-Les-Ouates, Geneva, Switzerland.
J Med Chem. 2004 Dec 30;47(27):6921-34. doi: 10.1021/jm031112e.
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.
c-Jun氨基末端激酶（JNKs）在包括细胞死亡（凋亡）相关疾病和炎症性疾病（癫痫、脑、心脏和肾脏缺血、神经退行性疾病、多发性硬化症、类风湿性关节炎和炎症性肠综合征）在内的多种疾病状态中起关键作用。对化合物库的筛选导致鉴定出一种2-（苯甲酰氨基甲基）噻吩磺酰胺（AS004509，化合物I）作为一种强效且选择性的JNK抑制剂。围绕这一新型激酶抑制基序进行的化学和构效关系（SAR）研究表明，分子的左侧和中部对于维持对该酶的活性至关重要。因此，我们研究了该分子右手部分多个变体的JNK抑制特性，这导致鉴定出2-（苯甲酰氨基甲基）噻吩磺酰胺苯并三唑（AS600292，化合物50a），这是该类中的首个强效且选择性的JNK抑制剂，它对生长因子和血清剥夺诱导的神经元细胞死亡具有保护作用。
