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


Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Shi, Q; Tebben, A; Dyckman, AJ; Li, H; Liu, C; Lin, J; Spergel, S; Burke, JR; McIntyre, KW; Olini, GC; Strnad, J; Surti, N; Muckelbauer, JK; Chang, C; An, Y; Cheng, L; Ruan, Q; Leftheris, K; Carter, PH; Tino, J; De Lucca, GV

Published Date

  • May 1, 2014

Published In

Volume / Issue

  • 24 / 9

Start / End Page

  • 2206 - 2211

PubMed ID

  • 24685542

Pubmed Central ID

  • 24685542

Electronic International Standard Serial Number (EISSN)

  • 1464-3405

Digital Object Identifier (DOI)

  • 10.1016/j.bmcl.2014.02.075


  • eng

Conference Location

  • England