Purine derivatives as potent Bruton’s tyrosine kinase (BTK) inhibitors for autoimmune diseases

Abstract

Investigation of various heterocyclic core isosteres of imidazopyrazines 1 &2 yielded purine derivatives 3 &8 as potent and selective BTK inhibitors. Subsequent SAR studies of the purine series led to the discovery of 20 as a leading compound. Compound 20 is very selective when screened against a panel of 400 kinases and is a potent inhibitor in cellular assays of human B cell function including B-Cell proliferation and CD86 cell surface expression and exhibited in vivo efficacy in a mouse PCA model. Its X-ray co-crystal structure with BTK shows that the high selectivity is gained from filling a BTK specific lipophilic pocket. However, physical and ADME properties leading to low oral exposure hindered further development.