Discovery of Chromane-6-Sulfonamide Derivative as a Potent, Selective, and Orally Available Novel Retinoic Acid Receptor-Related Orphan Receptor γt Inverse Agonist

Interleukin-17 (IL-17) is a proinflammatory
cytokine that plays
a dominant role in inflammation, autoimmunity, and host defense. RORγt
is a key transcription factor mediating T helper 17 (Th17) cell differentiation
and IL-17 production, which is able to activate CD8+ T
cells and elicit antitumor efficacy. A series of sulfonamide derivatives
as novel RORγt inverse agonists were designed and synthesized.
Using GSK2981278 (phase II) as a starting point, we engineered structural
modifications that significantly improved the activity and pharmacokinetic
profile. In animal studies, oral administration of compound d3 showed a robust and dose-dependent inhibition of the IL-17A
cytokine expression in a mouse imiquimod-induced skin inflammation
model. Docking analysis of the binding mode revealed that the compound d3 occupied the active pocket suitably. Thus, compound d3 was selected as a clinical compound for the treatment of
Th17-driven autoimmune diseases.

白细胞介素-17（Interleukin-17，IL-17）是一种促炎细胞因子，在炎症反应、自身免疫及宿主防御过程中发挥核心调控作用。维甲酸相关孤儿受体γt（RORγt）是介导辅助性T细胞17（T helper 17，Th17）分化与IL-17产生的关键转录因子，其可激活CD8+ T细胞并诱发抗肿瘤效应。本研究设计并合成了一系列作为新型RORγt反向激动剂的磺酰胺衍生物，以GSK2981278（II期临床试验阶段）为起始先导骨架，通过结构修饰显著提升了目标化合物的活性与药代动力学特性。动物实验结果显示，化合物d3经口服给药后，在咪喹莫特诱导的小鼠皮肤炎症模型中，对IL-17A细胞因子的表达展现出强效且剂量依赖性的抑制作用。结合模式的分子对接分析表明，化合物d3可合适地占据靶蛋白的活性口袋。综上，化合物d3被选为治疗Th17介导的自身免疫性疾病的临床候选化合物。