2-Phenylamino-6-cyano-1H-benzimidazole-based isoform selective casein kinase 1 gamma (CK1γ) inhibitors

• Published in: Bioorganic & medicinal chemistry letters 2012-09, Vol.22 (17), p.5392-5395
• Main Authors: Hua, Zihao, Huang, Xin, Bregman, Howard, Chakka, Nagasree, DiMauro, Erin F., Doherty, Elizabeth M., Goldstein, Jon, Gunaydin, Hakan, Huang, Hongbing, Mercede, Stephanie, Newcomb, John, Patel, Vinod F., Turci, Susan M., Yan, Jie, Wilson, Cindy, Martin, Matthew W.
• Format: Article
• Language: English
• Subjects: Animals; Benzimidazoles - chemistry; Benzimidazoles - pharmacokinetics; Benzimidazoles - pharmacology; beta Catenin - metabolism; Binding Sites; Biological and medical sciences; casein; Casein kinase 1; Casein kinase I; Casein Kinase I - antagonists & inhibitors; Casein Kinase I - chemistry; Casein Kinase I - metabolism; chemistry; GSK3β; Humans; Medical sciences; Mice; Models, Molecular; Pharmacokinetics; Pharmacology. Drug treatments; Protein Isoforms - antagonists & inhibitors; Protein Isoforms - metabolism; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacokinetics; Protein Kinase Inhibitors - pharmacology; Rats; screening; Structure-Activity Relationship; Wnt pathway; β-Catenin
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2012.07.046

Screening of the Amgen compound library led to the identification of 2-phenylamino-6-cyano-1H-benzimidazole 1a as a potent CK1 gamma inhibitor with excellent kinase selectivity and unprecedented CK1 isoform selectivity. Further structure-based optimization of this series resulted in the discovery of 1h which possessed good enzymatic and cellular potency, excellent CK1 isoform and kinase selectivity, and acceptable pharmacokinetic properties.