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

Journal Article · Thu May 01 04:00:00 EDT 2014 · Bioorganic & Medicinal Chemistry Letters

DOI:https://doi.org/10.1016/j.bmcl.2014.02.075· OSTI ID:1347759

Shi, Qing; Tebben, Andrew; Dyckman, Alaric J.; Li, Hedy; Liu, Chunjian; Lin, James; Spergel, Steve; Burke, James R.; McIntyre, Kim W.; Olini, Gilbert C.; Strnad, Joann; Surti, Neha; Muckelbauer, Jodi K.; Chang, Chiehying; An, Yongmi; Cheng, Lin; Ruan, Qian; Leftheris, Katerina; Carter, Percy H.; Tino, Joseph ; De Lucca, George V.

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.

• Research Organization: Advanced Photon Source (APS), Argonne National Laboratory (ANL), Argonne, IL (US)
• Sponsoring Organization: USDOE
• OSTI ID: 1347759
• Journal Information: Bioorganic & Medicinal Chemistry Letters, Journal Name: Bioorganic & Medicinal Chemistry Letters Journal Issue: 9 Vol. 24; ISSN 0960-894X
• Country of Publication: United States
• Language: ENGLISH

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60 APPLIED LIFE SCIENCES