Discovery of 8‑Amino-imidazo[1,5‑a]pyrazines as Reversible BTK Inhibitors for the Treatment of Rheumatoid Arthritis
journal contributionposted on 05.02.2016, 15:04 by Jian Liu, Deodial Guiadeen, Arto Krikorian, Xiaolei Gao, James Wang, Sobhana Babu Boga, Abdul-Basit Alhassan, Younong Yu, Henry Vaccaro, Shilan Liu, Chundao Yang, Hao Wu, Alan Cooper, Jos de Man, Allard Kaptein, Kevin Maloney, Viktor Hornak, Ying-Duo Gao, Thierry O. Fischmann, Hans Raaijmakers, Diep Vu-Pham, Jeremy Presland, My Mansueto, Zangwei Xu, Erica Leccese, Jie Zhang-Hoover, Ian Knemeyer, Charles G. Garlisi, Nathan Bays, Peter Stivers, Philip E. Brandish, Alexandra Hicks, Ronald Kim, Joseph A. Kozlowski
Bruton’s tyrosine kinase (BTK) is a Tec family kinase with a well-defined role in the B cell receptor (BCR) pathway. It has become an attractive kinase target for selective B cell inhibition and for the treatment of B cell related diseases. We report a series of compounds based on 8-amino-imidazo[1,5-a]pyrazine that are potent reversible BTK inhibitors with excellent kinase selectivity. Selectivity is achieved through specific interactions of the ligand with the kinase hinge and driven by aminopyridine hydrogen bondings with Ser538 and Asp539, and by hydrophobic interaction of trifluoropyridine in the back pocket. These interactions are evident in the X-ray crystal structure of the lead compounds 1 and 3 in the complex with the BTK enzyme. Our lead compounds show desirable PK profiles and efficacy in the preclinical rat collagen induced arthritis model.