Discovery of imidazo[1,5-a]pyridines and -pyrimidines as potent and selective RORc inverse agonists
Discovery of imidazo[1,5-a]pyridines and -pyrimidines as potent and selective RORc inverse agonists
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DOI：
10.1016/j.bmcl.2015.05.055
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发表时间：
2015-08-01
影响因子：
2.7
通讯作者：
Wong, Harvey
中科院分区：
文献类型：
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作者：
Fauber, Benjamin P.;Gobbi, Alberto;Wong, Harvey
核受体（NR）视黄酸受体相关孤儿受体γ（ROR γ、RORc或NR 1F 3）是治疗自身免疫性疾病的有希望的靶点。RORc是促炎细胞因子白细胞介素-17产生的关键调节因子。我们发现了一系列有效的和选择性的咪唑并[1，5-a]吡啶和嘧啶RORc反向激动剂。在我们的细胞选择性小组中，最有效的化合物显示出对RORc的选择性超过其他ROR家族成员、PPAR γ和NR的300倍。GNE-0946（9）和GNE-6468（28）的良好效力、选择性和理化性质，以及其对人原代细胞中IL-17产生的强效抑制作用，支持其用作化学生物学工具，以进一步探索RORc在人类生物学中的作用。(C)2015爱思唯尔有限公司版权所有。
The nuclear receptor (NR) retinoic acid receptor-related orphan receptor gamma (ROR gamma, RORc, or NR1F3) is a promising target for the treatment of autoimmune diseases. RORc is a critical regulator in the production of the pro-inflammatory cytokine interleukin-17. We discovered a series of potent and selective imidazo[1,5-a]pyridine and -pyrimidine RORc inverse agonists. The most potent compounds displayed >300-fold selectivity for RORc over the other ROR family members, PPAR gamma, and NRs in our cellular selectivity panel. The favorable potency, selectivity, and physiochemical properties of GNE-0946 (9) and GNE-6468 (28), in addition to their potent suppression of IL-17 production in human primary cells, support their use as chemical biology tools to further explore the role of RORc in human biology. (C) 2015 Elsevier Ltd. All rights reserved.