Discovery of potent and selective reversible Bruton's tyrosine kinase inhibitors. (15th June 2021)

• Record Type: Journal Article
• Authors: Qiu, Hui; Ali, Zahid; Bender, Andrew; Caldwell, Richard; Chen, Yi-Ying; Fang, Zhizhou; Gardberg, Anna; Glaser, Nina; Goettsche, Anja; Goutopoulos, Andreas; Grenningloh, Roland; Hanschke, Bettina; Head, Jared; Johnson, Theresa; Jones, Christopher; Jones, Reinaldo; Kulkarni, Shashank; Maurer, Christine; Morandi, Federica; Neagu, Constantin; Poetzsch, Sven; Potnick, Justin; Schmidt, Ralf; Roe, Katherine; Viacava Follis, Ariele; Wing, Carolyn; Zhu, Xiaohua; Sherer, Brian
• Is Part Of: Bioorganic & medicinal chemistry. Volume 40(2021)
• Publication Date: 2021-06-15
• Subjects: Reversible BTK inhibitor -- Bruton's tyrosine kinase -- Selective -- H3 selectivity pocket; ACN acetonitrile -- BTK Bruton's tyrosine kinase -- CIA collagen-induced arthritis -- DCM dichloromethane -- dppf 1, 1′-bis(diphenylphosphino)ferrocene -- Fsp3 the fraction of sp3 carbon atoms -- PBMC peripheral blood mononuclear cell -- PK pharmacokinetics -- QD once a day -- SAR structure-activity relationship -- SFC super fluid chromatography -- TEA triethylamine; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2021.116163
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: Bruton's tyrosine kinase (BTK) is a cytoplasmic, non-receptor tyrosine kinase member of the TEC family of tyrosine kinases. Pre-clinical and clinical data have shown that targeting BTK can be used for the treatment for B-cell disorders. Here we disclose the discovery of a novel imidazo[4, 5- b ]pyridine series of potent, selective reversible BTK inhibitors through a rational design approach. From a starting hit molecule 1, medicinal chemistry optimization led to the development of a lead compound 30, which exhibited 58 nM BTK inhibitory potency in human whole blood and high kinome selectivity. Additionally, the compound demonstrated favorable pharmacokinetics (PK), and showed potent dose-dependent efficacy in a rat CIA model.