在大鼠药代动力学/药效学模型中具有活性的口服生物可利用的脾酪氨酸激酶抑制剂。
Orally bioavailable Syk inhibitors with activity in a rat PK/PD model.
作者信息
Thoma Gebhard, Veenstra Siem, Strang Ross, Blanz Joachim, Vangrevelinghe Eric, Berghausen Jörg, Lee Christian C, Zerwes Hans-Günter
机构信息
Global Discovery Chemistry, Novartis Institutes for Biomedical Research, 4056 Basel, Switzerland.
Global Discovery Chemistry, Novartis Institutes for Biomedical Research, 4056 Basel, Switzerland.
出版信息
Bioorg Med Chem Lett. 2015 Oct 15;25(20):4642-7. doi: 10.1016/j.bmcl.2015.08.037. Epub 2015 Aug 18.
Design and optimization of benzo- and pyrido-thiazoles/isothiazoles are reported leading to the discovery of the potent, orally bioavailable Syk inhibitor 5, which was found to be active in a rat PK/PD model. Compound 5 showed acceptable overall kinase selectivity. However, in addition to Syk it also inhibited Aurora kinase in enzymatic and cellular settings leading to findings in the micronucleus assay. As a consequence, compound 5 was not further pursued.
报道了苯并噻唑和吡啶并噻唑/异噻唑的设计与优化，从而发现了强效的、口服生物可利用的脾酪氨酸激酶（Syk）抑制剂5，该抑制剂在大鼠药代动力学/药效学（PK/PD）模型中具有活性。化合物5表现出可接受的总体激酶选择性。然而，除Syk外，它在酶促和细胞环境中还抑制极光激酶，导致微核试验出现相关结果。因此，未对化合物5进行进一步研究。
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