Design and optimization of a series of 4-(3-azabicyclo[3.1.0]hexan-3-yl) pyrimidin-2-amines: Dual inhibitors of TYK2 and JAK1
Design and optimization of a series of 4-(3-azabicyclo[3.1.0]hexan-3-yl) pyrimidin-2-amines: Dual inhibitors of TYK2 and JAK1
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DOI：
10.1016/j.bmc.2020.115481
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发表时间：
2020-05-15
影响因子：
3.5
通讯作者：
Yang, Xin
中科院分区：
文献类型：
--
作者：
Fensome, Andrew;Ambler, Catherine M.;Yang, Xin
在这里，我们公开了一系列新的基于3.1.0氮杂双环取代的嘧啶支架的TYK2/JAK1抑制剂。我们举例说明了使用基于结构的药物设计来进行这一系列化合物的初始设计和后续优化。一个先进的例子19达到了效力、选择性和ADME的计划目标，并在佐剂诱导的关节炎大鼠模型中展示了口服活性。
Herein, we disclose a new series of TYK2/ JAK1 inhibitors based upon a 3.1.0 azabicyclic substituted pyrimidine scaffold. We illustrate the use of structure-based drug design for the initial design and subsequent optimization of this series of compounds. One advanced example 19 met program objectives for potency, selectivity and ADME, and demonstrated oral activity in the adjuvant-induced arthritis rat model.