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Discovery of 8-Amino-imidazo[1,5-a]pyrazines as Reversible BTK Inhibitors for the Treatment of Rheumatoid Arthritis.

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.

SUBMITTER: Liu J 

PROVIDER: S-EPMC4753550 | biostudies-literature | 2016 Feb

REPOSITORIES: biostudies-literature

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Discovery of 8-Amino-imidazo[1,5-a]pyrazines as Reversible BTK Inhibitors for the Treatment of Rheumatoid Arthritis.

Liu Jian J   Guiadeen Deodial D   Krikorian Arto A   Gao Xiaolei X   Wang James J   Boga Sobhana Babu SB   Alhassan Abdul-Basit AB   Yu Younong Y   Vaccaro Henry H   Liu Shilan S   Yang Chundao C   Wu Hao H   Cooper Alan A   de Man Jos J   Kaptein Allard A   Maloney Kevin K   Hornak Viktor V   Gao Ying-Duo YD   Fischmann Thierry O TO   Raaijmakers Hans H   Vu-Pham Diep D   Presland Jeremy J   Mansueto My M   Xu Zangwei Z   Leccese Erica E   Zhang-Hoover Jie J   Knemeyer Ian I   Garlisi Charles G CG   Bays Nathan N   Stivers Peter P   Brandish Philip E PE   Hicks Alexandra A   Kim Ronald R   Kozlowski Joseph A JA  

ACS medicinal chemistry letters 20151219 2

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 aminop  ...[more]

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