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

Autor: Liu J; Department of Early Development and Discovery Sciences, Merck Research Laboratories , 126 East Lincoln Avenue, Rahway, New Jersey 07065, United States., Guiadeen D; Department of Early Development and Discovery Sciences, Merck Research Laboratories , 126 East Lincoln Avenue, Rahway, New Jersey 07065, United States., Krikorian A; Department of Early Development and Discovery Sciences, Merck Research Laboratories , 126 East Lincoln Avenue, Rahway, New Jersey 07065, United States., Gao X; Department of Early Development and Discovery Sciences, Merck Research Laboratories , 126 East Lincoln Avenue, Rahway, New Jersey 07065, United States., Wang J; Department of Early Development and Discovery Sciences, Merck Research Laboratories , 126 East Lincoln Avenue, Rahway, New Jersey 07065, United States., Boga SB; Department of Early Development and Discovery Sciences, Merck Research Laboratories , 126 East Lincoln Avenue, Rahway, New Jersey 07065, United States., Alhassan AB; Department of Early Development and Discovery Sciences, Merck Research Laboratories , 126 East Lincoln Avenue, Rahway, New Jersey 07065, United States., Yu Y; Department of Early Development and Discovery Sciences, Merck Research Laboratories , 126 East Lincoln Avenue, Rahway, New Jersey 07065, United States., Vaccaro H; Department of Early Development and Discovery Sciences, Merck Research Laboratories , 126 East Lincoln Avenue, Rahway, New Jersey 07065, United States., Liu S; WuXi PharmaTech Co. Ltd , 288 FuTe Zhong Road, No. 1 Building, WaiGaoQiao Free Trade Zone, Shanghai 200131, P. R. China., Yang C; WuXi PharmaTech Co. Ltd , 288 FuTe Zhong Road, No. 1 Building, WaiGaoQiao Free Trade Zone, Shanghai 200131, P. R. China., Wu H; WuXi PharmaTech Co. Ltd , 288 FuTe Zhong Road, No. 1 Building, WaiGaoQiao Free Trade Zone, Shanghai 200131, P. R. China., Cooper A; Department of Early Development and Discovery Sciences, Merck Research Laboratories , 126 East Lincoln Avenue, Rahway, New Jersey 07065, United States., de Man J; Department of Early Development and Discovery Sciences, Merck Research Laboratories , 126 East Lincoln Avenue, Rahway, New Jersey 07065, United States., Kaptein A; Department of Early Development and Discovery Sciences, Merck Research Laboratories , 126 East Lincoln Avenue, Rahway, New Jersey 07065, United States., Maloney K; Department of Early Development and Discovery Sciences, Merck Research Laboratories , 126 East Lincoln Avenue, Rahway, New Jersey 07065, United States., Hornak V; Department of Early Development and Discovery Sciences, Merck Research Laboratories , 126 East Lincoln Avenue, Rahway, New Jersey 07065, United States., Gao YD; Department of Early Development and Discovery Sciences, Merck Research Laboratories , 126 East Lincoln Avenue, Rahway, New Jersey 07065, United States., Fischmann TO; Department of Early Development and Discovery Sciences, Merck Research Laboratories , 126 East Lincoln Avenue, Rahway, New Jersey 07065, United States., Raaijmakers H; Department of Early Development and Discovery Sciences, Merck Research Laboratories , 126 East Lincoln Avenue, Rahway, New Jersey 07065, United States., Vu-Pham D; Department of Early Development and Discovery Sciences, Merck Research Laboratories , 126 East Lincoln Avenue, Rahway, New Jersey 07065, United States., Presland J; Department of Early Development and Discovery Sciences, Merck Research Laboratories , 126 East Lincoln Avenue, Rahway, New Jersey 07065, United States., Mansueto M; Department of Early Development and Discovery Sciences, Merck Research Laboratories , 126 East Lincoln Avenue, Rahway, New Jersey 07065, United States., Xu Z; Department of Early Development and Discovery Sciences, Merck Research Laboratories , 126 East Lincoln Avenue, Rahway, New Jersey 07065, United States., Leccese E; Department of Early Development and Discovery Sciences, Merck Research Laboratories , 126 East Lincoln Avenue, Rahway, New Jersey 07065, United States., Zhang-Hoover J; Department of Early Development and Discovery Sciences, Merck Research Laboratories , 126 East Lincoln Avenue, Rahway, New Jersey 07065, United States., Knemeyer I; Department of Early Development and Discovery Sciences, Merck Research Laboratories , 126 East Lincoln Avenue, Rahway, New Jersey 07065, United States., Garlisi CG; Department of Early Development and Discovery Sciences, Merck Research Laboratories , 126 East Lincoln Avenue, Rahway, New Jersey 07065, United States., Bays N; Department of Early Development and Discovery Sciences, Merck Research Laboratories , 126 East Lincoln Avenue, Rahway, New Jersey 07065, United States., Stivers P; Department of Early Development and Discovery Sciences, Merck Research Laboratories , 126 East Lincoln Avenue, Rahway, New Jersey 07065, United States., Brandish PE; Department of Early Development and Discovery Sciences, Merck Research Laboratories , 126 East Lincoln Avenue, Rahway, New Jersey 07065, United States., Hicks A; Department of Early Development and Discovery Sciences, Merck Research Laboratories , 126 East Lincoln Avenue, Rahway, New Jersey 07065, United States., Kim R; Department of Early Development and Discovery Sciences, Merck Research Laboratories , 126 East Lincoln Avenue, Rahway, New Jersey 07065, United States., Kozlowski JA; Department of Early Development and Discovery Sciences, Merck Research Laboratories , 126 East Lincoln Avenue, Rahway, New Jersey 07065, United States.
Jazyk: angličtina
Zdroj: ACS medicinal chemistry letters [ACS Med Chem Lett] 2015 Dec 19; Vol. 7 (2), pp. 198-203. Date of Electronic Publication: 2015 Dec 19 (Print Publication: 2016).
DOI: 10.1021/acsmedchemlett.5b00463
Abstrakt: 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.
Databáze: MEDLINE
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