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  • Title: Potent, non-covalent reversible BTK inhibitors with 8-amino-imidazo[1,5-a]pyrazine core featuring 3-position bicyclic ring substitutes.
    Author: Liu J, Guiadeen D, Krikorian A, Gao X, Wang J, Babu Boga S, Alhassan AB, Yu W, Selyutin O, Yu Y, Anand R, Xu J, Kelly J, Duffy JL, Liu S, Yang C, Wu H, Cai J, Bennett C, Maloney KM, Tyagarajan S, Gao YD, Fischmann TO, Presland J, Mansueto M, Xu Z, Leccese E, Zhang-Hoover J, Knemeyer I, Garlisi CG, Stivers P, Brandish PE, Hicks A, Kim R, Kozlowski JA.
    Journal: Bioorg Med Chem Lett; 2020 Sep 01; 30(17):127390. PubMed ID: 32738973.
    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. Many BTK inhibitors have been discovered for the treatment of cancer and rheumatoid arthritis, including a series of BTK inhibitors based on 8-amino-imidazo[1,5-a]pyrazine we recently reported. The X-ray crystal structures of BTK with inhibitors were also published, which provided great help for the SAR design. Here we report our SAR work introducing ring constraints for the 3-position piperidine amides on the BTK inhibitors based on 8-amino-imidazo[1,5-a]pyrazine. This modification improved the potency in BTK inhibitions, as well as the PK profile and the off-target selectivity. The dose-dependent efficacy of two BTK inhibitors was observed in the rat collagen induced arthritis (CIA) model.
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