| Literature DB >> 26985298 |
Jian Liu1, Deodial Guiadeen1, Arto Krikorian1, Xiaolei Gao1, James Wang1, Sobhana Babu Boga1, Abdul-Basit Alhassan1, Younong Yu1, Henry Vaccaro1, Shilan Liu2, Chundao Yang2, Hao Wu2, Alan Cooper1, Jos de Man1, Allard Kaptein1, Kevin Maloney1, Viktor Hornak1, Ying-Duo Gao1, Thierry O Fischmann1, Hans Raaijmakers1, Diep Vu-Pham1, Jeremy Presland1, My Mansueto1, Zangwei Xu1, Erica Leccese1, Jie Zhang-Hoover1, Ian Knemeyer1, Charles G Garlisi1, Nathan Bays1, Peter Stivers1, Philip E Brandish1, Alexandra Hicks1, Ronald Kim1, Joseph A Kozlowski1.
Abstract
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.Entities:
Keywords: BTK; X-ray crystal structure; human peripheral blood mononuclear cells (hPBMC); kinase selectivity; pharmacokinetic; rat CIA model; rheumatoid arthritis (RA); whole blood
Year: 2015 PMID： 26985298 PMCID： PMC4753550 DOI： 10.1021/acsmedchemlett.5b00463
Source DB: PubMed Journal: ACS Med Chem Lett ISSN： 1948-5875 Impact factor: 4.345