Discovery of 3-alkyl-5-aryl-1-pyrimidyl-1H-pyrazole derivatives as a novel selective inhibitor scaffold of JNK3. (1st January 2020)

• Record Type: Journal Article
• Authors: Oh, Youri; Jang, Miyoung; Cho, Hyunwook; Yang, Songyi; Im, Daseul; Moon, Hyungwoo; Hah, Jung-Mi
• Is Part Of: Journal of enzyme inhibition and medicinal chemistry. Volume 35:Number 1(2020)
• Page Start: 372
• Page End: 376
• Publication Date: 2020-01-01
• Subjects: JNK -- pyrazole -- neurodegenerative diseases -- SAR; Enzyme inhibitors -- Periodicals; Enzyme Inhibitors -- periodicals; Biochemistry -- periodicals; 572.7
• DOI: 10.1080/14756366.2019.1705294
• Languages: English
• ISSNs: 1475-6366

Abstract

Abstract: 3-alkyl-5-aryl-1-pyrimidyl-1 H -pyrazole derivatives were designed and synthesised as selective inhibitors of JNK3, a target for the treatment of neurodegenerative diseases. Following previous studies, we have designed JNK3 inhibitors to reduce the molecular weight and successfully identified a lead compound that exhibits equipotent activity towards JNK3. Kinase profiling results also showed high selectivity for JNK3 among 38 kinases. Among the derivatives, the IC50 value of 8a, ( R )-2-(1-(2-((1-(cyclopropanecarbonyl)pyrrolidin-3-yl)amino)pyrimidin-4-yl)-5-(3, 4-dichlorophenyl)-1 H -pyrazol-3-yl)acetonitrile exhibited 227 nM, showing the highest inhibitory activity against JNK3.