Lead identification of novel and selective TYK2 inhibitors
Lead identification of novel and selective TYK2 inhibitors
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DOI：
10.1016/j.ejmech.2013.03.070
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发表时间：
2013-09-01
影响因子：
6.7
通讯作者：
Magnuson, Steven
中科院分区：
文献类型：
--
作者：
Liang, Jun;Tsui, Vickie;Magnuson, Steven
提出了一种治疗原理，通过选择性靶向TYK2治疗炎性疾病，如牛皮癣和炎症性肠病（IBD）。Hit triage，在对TYK2抑制剂进行高通量筛选后，发现吡啶I是一种很有希望的先导物鉴定起点。分子的3个独立区域的初始扩张导致最终鉴定出环丙酰胺46，这是一种有效的铅类似物，具有良好的激酶选择性，物理化学性质和药代动力学特征。通过分析该序列在TYK2和JAK2晶体结构中的结合模式，揭示了导致良好TYK2效力的关键相互作用，并为未来优化选择性提供了设计选项。(C) 2013 Elsevier Masson SAS。版权所有。
A therapeutic rationale is proposed for the treatment of inflammatory diseases, such as psoriasis and inflammatory bowel diseases (IBD), by selective targeting of TYK2. Hit triage, following a high-throughput screen for TYK2 inhibitors, revealed pyridine I as a promising starting point for lead identification. Initial expansion of 3 separate regions of the molecule led to eventual identification of cyclopropyl amide 46, a potent lead analog with good kinase selectivity, physicochemical properties, and pharmacokinetic profile. Analysis of the binding modes of the series in TYK2 and JAK2 crystal structures revealed key interactions leading to good TYK2 potency and design options for future optimization of selectivity. (C) 2013 Elsevier Masson SAS. All rights reserved.