title: 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.
authors.affiliation: Department of Early Development and Discovery Sciences, Merck Research Laboratories , 126 East Lincoln Avenue, Rahway, New Jersey 07065, United States.
authors.forename: Jian
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Early Development and Discovery Sciences, Merck Research Laboratories , 126 East Lincoln Avenue, Rahway, New Jersey 07065, United States.
authors.forename: Deodial
authors.initials: D
authors.lastname: Guiadeen
authors.affiliation: Department of Early Development and Discovery Sciences, Merck Research Laboratories , 126 East Lincoln Avenue, Rahway, New Jersey 07065, United States.
authors.forename: Arto
authors.initials: A
authors.lastname: Krikorian
authors.affiliation: Department of Early Development and Discovery Sciences, Merck Research Laboratories , 126 East Lincoln Avenue, Rahway, New Jersey 07065, United States.
authors.forename: Xiaolei
authors.initials: X
authors.lastname: Gao
authors.affiliation: Department of Early Development and Discovery Sciences, Merck Research Laboratories , 126 East Lincoln Avenue, Rahway, New Jersey 07065, United States.
authors.forename: James
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Early Development and Discovery Sciences, Merck Research Laboratories , 126 East Lincoln Avenue, Rahway, New Jersey 07065, United States.
authors.forename: Sobhana Babu
authors.initials: SB
authors.lastname: Boga
authors.affiliation: Department of Early Development and Discovery Sciences, Merck Research Laboratories , 126 East Lincoln Avenue, Rahway, New Jersey 07065, United States.
authors.forename: Abdul-Basit
authors.initials: AB
authors.lastname: Alhassan
authors.affiliation: Department of Early Development and Discovery Sciences, Merck Research Laboratories , 126 East Lincoln Avenue, Rahway, New Jersey 07065, United States.
authors.forename: Younong
authors.initials: Y
authors.lastname: Yu
authors.affiliation: Department of Early Development and Discovery Sciences, Merck Research Laboratories , 126 East Lincoln Avenue, Rahway, New Jersey 07065, United States.
authors.forename: Henry
authors.initials: H
authors.lastname: Vaccaro
authors.affiliation: WuXi PharmaTech Co. Ltd , 288 FuTe Zhong Road, No. 1 Building, WaiGaoQiao Free Trade Zone, Shanghai 200131, P. R. China.
authors.forename: Shilan
authors.initials: S
authors.lastname: Liu
authors.affiliation: WuXi PharmaTech Co. Ltd , 288 FuTe Zhong Road, No. 1 Building, WaiGaoQiao Free Trade Zone, Shanghai 200131, P. R. China.
authors.forename: Chundao
authors.initials: C
authors.lastname: Yang
authors.affiliation: WuXi PharmaTech Co. Ltd , 288 FuTe Zhong Road, No. 1 Building, WaiGaoQiao Free Trade Zone, Shanghai 200131, P. R. China.
authors.forename: Hao
authors.initials: H
authors.lastname: Wu
authors.affiliation: Department of Early Development and Discovery Sciences, Merck Research Laboratories , 126 East Lincoln Avenue, Rahway, New Jersey 07065, United States.
authors.forename: Alan
authors.initials: A
authors.lastname: Cooper
authors.affiliation: Department of Early Development and Discovery Sciences, Merck Research Laboratories , 126 East Lincoln Avenue, Rahway, New Jersey 07065, United States.
authors.forename: Jos
authors.initials: J
authors.lastname: de Man
authors.affiliation: Department of Early Development and Discovery Sciences, Merck Research Laboratories , 126 East Lincoln Avenue, Rahway, New Jersey 07065, United States.
authors.forename: Allard
authors.initials: A
authors.lastname: Kaptein
authors.affiliation: Department of Early Development and Discovery Sciences, Merck Research Laboratories , 126 East Lincoln Avenue, Rahway, New Jersey 07065, United States.
authors.forename: Kevin
authors.initials: K
authors.lastname: Maloney
authors.affiliation: Department of Early Development and Discovery Sciences, Merck Research Laboratories , 126 East Lincoln Avenue, Rahway, New Jersey 07065, United States.
authors.forename: Viktor
authors.initials: V
authors.lastname: Hornak
authors.affiliation: Department of Early Development and Discovery Sciences, Merck Research Laboratories , 126 East Lincoln Avenue, Rahway, New Jersey 07065, United States.
authors.forename: Ying-Duo
authors.initials: YD
authors.lastname: Gao
authors.affiliation: Department of Early Development and Discovery Sciences, Merck Research Laboratories , 126 East Lincoln Avenue, Rahway, New Jersey 07065, United States.
authors.forename: Thierry O
authors.initials: TO
authors.lastname: Fischmann
authors.affiliation: Department of Early Development and Discovery Sciences, Merck Research Laboratories , 126 East Lincoln Avenue, Rahway, New Jersey 07065, United States.
authors.forename: Hans
authors.initials: H
authors.lastname: Raaijmakers
authors.affiliation: Department of Early Development and Discovery Sciences, Merck Research Laboratories , 126 East Lincoln Avenue, Rahway, New Jersey 07065, United States.
authors.forename: Diep
authors.initials: D
authors.lastname: Vu-Pham
authors.affiliation: Department of Early Development and Discovery Sciences, Merck Research Laboratories , 126 East Lincoln Avenue, Rahway, New Jersey 07065, United States.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Presland
authors.affiliation: Department of Early Development and Discovery Sciences, Merck Research Laboratories , 126 East Lincoln Avenue, Rahway, New Jersey 07065, United States.
authors.forename: My
authors.initials: M
authors.lastname: Mansueto
authors.affiliation: Department of Early Development and Discovery Sciences, Merck Research Laboratories , 126 East Lincoln Avenue, Rahway, New Jersey 07065, United States.
authors.forename: Zangwei
authors.initials: Z
authors.lastname: Xu
authors.affiliation: Department of Early Development and Discovery Sciences, Merck Research Laboratories , 126 East Lincoln Avenue, Rahway, New Jersey 07065, United States.
authors.forename: Erica
authors.initials: E
authors.lastname: Leccese
authors.affiliation: Department of Early Development and Discovery Sciences, Merck Research Laboratories , 126 East Lincoln Avenue, Rahway, New Jersey 07065, United States.
authors.forename: Jie
authors.initials: J
authors.lastname: Zhang-Hoover
authors.affiliation: Department of Early Development and Discovery Sciences, Merck Research Laboratories , 126 East Lincoln Avenue, Rahway, New Jersey 07065, United States.
authors.forename: Ian
authors.initials: I
authors.lastname: Knemeyer
authors.affiliation: Department of Early Development and Discovery Sciences, Merck Research Laboratories , 126 East Lincoln Avenue, Rahway, New Jersey 07065, United States.
authors.forename: Charles G
authors.initials: CG
authors.lastname: Garlisi
authors.affiliation: Department of Early Development and Discovery Sciences, Merck Research Laboratories , 126 East Lincoln Avenue, Rahway, New Jersey 07065, United States.
authors.forename: Nathan
authors.initials: N
authors.lastname: Bays
authors.affiliation: Department of Early Development and Discovery Sciences, Merck Research Laboratories , 126 East Lincoln Avenue, Rahway, New Jersey 07065, United States.
authors.forename: Peter
authors.initials: P
authors.lastname: Stivers
authors.affiliation: Department of Early Development and Discovery Sciences, Merck Research Laboratories , 126 East Lincoln Avenue, Rahway, New Jersey 07065, United States.
authors.forename: Philip E
authors.initials: PE
authors.lastname: Brandish
authors.affiliation: Department of Early Development and Discovery Sciences, Merck Research Laboratories , 126 East Lincoln Avenue, Rahway, New Jersey 07065, United States.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Hicks
authors.affiliation: Department of Early Development and Discovery Sciences, Merck Research Laboratories , 126 East Lincoln Avenue, Rahway, New Jersey 07065, United States.
authors.forename: Ronald
authors.initials: R
authors.lastname: Kim
authors.affiliation: Department of Early Development and Discovery Sciences, Merck Research Laboratories , 126 East Lincoln Avenue, Rahway, New Jersey 07065, United States.
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Kozlowski
keywords: BTK; X-ray crystal structure; human peripheral blood mononuclear cells (hPBMC); kinase selectivity; pharmacokinetic; rat CIA model; rheumatoid arthritis (RA); whole blood