N-(3-Cyano-4,5,6,7-tetrahydro-1-benzothien-2-yl)amides as potent, selective, inhibitors of JNK2 and JNK3

• Published in: Bioorganic & medicinal chemistry letters 2007-03, Vol.17 (5), p.1296-1301
• Main Authors: Angell, Richard M., Atkinson, Francis L., Brown, Murray J., Chuang, Tsu Tshen, Christopher, John A., Cichy-Knight, Maria, Dunn, Allison K., Hightower, Kendra E., Malkakorpi, Susanna, Musgrave, James R., Neu, Margarete, Rowland, Paul, Shea, Robyn L., Smith, Jeffery L., Somers, Donald O., Thomas, Sonia A., Thompson, Gladstone, Wang, Ruolan
• Format: Article
• Language: English
• Subjects: Amides - chemical synthesis; Amides - chemistry; Amides - pharmacology; Benzene Derivatives - chemical synthesis; Benzene Derivatives - chemistry; Benzene Derivatives - pharmacology; Binding Sites; Biological and medical sciences; Crystallography, X-Ray; Humans; Inhibitor; JNK; JNK3; Kinase; MAPK; Medical sciences; Miscellaneous; Mitogen-Activated Protein Kinase 10 - antagonists & inhibitors; Mitogen-Activated Protein Kinase 10 - chemistry; Mitogen-Activated Protein Kinase 9 - antagonists & inhibitors; Mitogen-Activated Protein Kinase 9 - chemistry; Pharmacology. Drug treatments; Selective; Structure-Activity Relationship
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2006.12.003

The identification and exploration of a novel, potent and selective series of N-(3-cyano-4,5,6,7-tetrahydro-1-benzothien-2-yl)amide inhibitors of JNK2 and JNK3 kinases is described. Compounds 5a and 11a were identified as potent inhibitors of JNK3 (pIC 50 6.7 and 6.6, respectively), with essentially equal potency against JNK2 (pIC 50 6.5). Selectivity within the mitogen-activated protein kinase (MAPK) family, against JNK1, p38α and ERK2, was observed for the series. X-ray crystallography of 5e and 8a in JNK3 revealed a unique binding mode, with the 3-cyano substituent forming an H-bond acceptor interaction with the hinge region of the ATP-binding site. The identification and exploration of a novel, potent and selective series of N-(3-cyano-4,5,6,7-tetrahydro-1-benzothien-2-yl)amide inhibitors of JNK2 and JNK3 kinases is described. Compounds 5a and 11a were identified as potent inhibitors of JNK3 (pIC 50 6.7 and 6.6, respectively), with essentially equal potency against JNK2 (pIC 50 6.5). Selectivity within the mitogen-activated protein kinase (MAPK) family, against JNK1, p38α and ERK2, was observed for the series. X-ray crystallography of 5e and 8a in JNK3 revealed a unique binding mode, with the 3-cyano substituent forming an H-bond acceptor interaction with the hinge region of the ATP-binding site.