Discovery of 3-morpholino-imidazole[1, 5-a]pyrazine BTK inhibitors for rheumatoid arthritis. Issue 16 (15th August 2017)

• Record Type: Journal Article
• Authors: Boga, Sobhana Babu; Alhassan, Abdul-Basit; Liu, Jian; Guiadeen, Deodial; Krikorian, Arto; Gao, Xiaolei; Wang, James; Yu, Younong; Anand, Rajan; Liu, Shilan; Yang, Chundao; Wu, Hao; Cai, Jiaqiang; Zhu, Hugh; Desai, Jagdish; Maloney, Kevin; Gao, Ying-Duo; Fischmann, Thierry O.; Presland, Jeremy; Mansueto, My; Xu, Zangwei; Leccese, Erica; Knemeyer, Ian; Garlisi, Charles G.; Bays, Nathan; Stivers, Peter; Brandish, Philip E.; Hicks, Alexandra; Cooper, Alan; Kim, Ronald M.; Kozlowski, Joseph A.;
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 27:Issue 16(2017)
• Page Start: 3939
• Page End: 3943
• Publication Date: 2017-08-15
• Subjects: BTK inhibitor -- ATP ribose pocket -- Rheumatoid arthritis -- Kinase selectivity -- Immunology; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2017.03.040
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: 8-Amino-imidazo[1, 5- a ]pyrazine-based Bruton's tyrosine kinase (BTK) inhibitors, such as6, exhibited potent inhibition of BTK but required improvements in both kinase and hERG selectivity (Liu et al., 2016; Gao et al., 2017). In an effort to maintain the inhibitory activity of these analogs and improve their selectivity profiles, we carried out SAR exploration of groups at the 3-position of pyrazine compound6 . This effort led to the discovery of the morpholine group as an optimized pharmacophore. Compounds13, 23 and38 displayed excellent BTK potencies, kinase and hERG selectivities, and pharmacokinetic profiles.