Open AccessDiscovery of 8-Amino-imidazo[1,5-a]pyrazines as Reversible BTK Inhibitors for the Treatment of Rheumatoid Arthritis
Author(s) -
Jian Liu,
Deodial Guiadeen,
A. D. Krikorian,
Xiaolei Gao,
James Wang,
Sobhana Babu Boga,
Abdul-Basit Alhassan,
Youg Yu,
Henry Vaccaro,
Shilan Liu,
Chundao Yang,
Hao Wu,
Alan Cooper,
Jos de Man,
Allard Kaptein,
Kevin M. Maloney,
Viktor Horn̆ák,
YingDuo Gao,
Thierry O. Fischmann,
H.C.A. Raaijmakers,
Diep VuPham,
Jeremy Presland,
My Sam 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
Publication year - 2015
Publication title -
acs medicinal chemistry letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.065
H-Index - 66
ISSN - 1948-5875
DOI - 10.1021/acsmedchemlett.5b00463
Subject(s) - bruton's tyrosine kinase , tyrosine kinase , kinase , chemistry , breakpoint cluster region , rheumatoid arthritis , selectivity , pyrazine , transferase , cancer research , biochemistry , enzyme , signal transduction , stereochemistry , pharmacology , medicine , receptor , immunology , catalysis
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.