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A novel series of cysteine-dependent, allosteric inverse agonists of the nuclear receptor RORγt.
Bioorganic & Medicinal Chemistry Letters ( IF 2.5 ) Pub Date : 2020-01-15 , DOI: 10.1016/j.bmcl.2020.126967
Xin Jiang 1 , Irina Dulubova 1 , Scott A Reisman 1 , Martha Hotema 1 , Chun-Yue I Lee 1 , Liping Liu 1 , Lyndsey McCauley 1 , Isaac Trevino 1 , Deborah A Ferguson 1 , Yigitcan Eken 2 , Angela K Wilson 2 , W Christian Wigley 1 , Melean Visnick 1
Affiliation  

Inhibition of the nuclear receptor Retinoic Acid Receptor-Related Orphan Receptor γt (RORγt) is a promising strategy for the treatment of autoimmune diseases. In this paper, we describe a series of allosteric, cysteine-dependent, inverse agonists of RORγt. Site-directed mutagenesis and molecular dynamics simulations are supportive of a mechanism of action through specific binding to Cys476 on alpha helix 11 of the ligand binding domain (LBD). Representative compounds in the series selectively inhibit RORγt, potently suppress interleukin-17A (IL-17A) production by human CD4+ T cells, and inhibit T helper 17 (Th17) differentiation from human naïve CD4+ T cells. The advanced compound 13 is orally bioavailable and active at a dose of 3 mg/kg in a murine collagen-induced model of rheumatoid arthritis. Collectively, these data are supportive of the development of compound 13 in autoimmune diseases.

中文翻译:

一系列新的半胱氨酸依赖性核受体RORγt的变构逆激动剂。

抑制核受体视黄酸受体相关的孤儿受体γt(RORγt)是一种治疗自身免疫性疾病的有前途的策略。在本文中,我们描述了一系列RORγt的变构,半胱氨酸依赖性逆激动剂。定点诱变和分子动力学模拟通过与配体结合域(LBD)的α螺旋11上的Cys476特异性结合来支持作用机制。该系列中的代表性化合物选择性抑制RORγt,有效抑制人CD4 + T细胞产生白介素17A(IL-17A),并抑制人CD4 + T细胞与T辅助蛋白17(Th17)的分化。在鼠类胶原诱导的类风湿性关节炎模型中,高级化合物13具有口服生物利用度,并具有3 mg / kg的剂量活性。总的来说,
更新日期:2020-01-15
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