多项证据表明，视黄酸相关孤儿核受体 γ t (RORγt) 是炎症性肠病 (IBD) 的有效治疗靶点。然而，系统性阻断RORγt很容易导致胸腺淋巴瘤和肝功能异常。因此，肠道限制性 RORγt 拮抗剂的开发可能会导致创新性 IBD 疗法的开发，从而提高安全性并保持有效性。我们发现了 SPH7854，一种有效的选择性 RORγt 拮抗剂。在小鼠和人类原代细胞中评估了 SPH7854 对辅助性 T 1 (Th1)/Th17/调节性 T (Treg) 细胞分化的影响。 SPH7854 (2-(4-(乙基磺酰基)苯基)-N-(6-(2-甲基-2-(吡啶-2-基)丙酰基)吡啶-3-基)乙酰胺)剂量依赖性抑制白介素-17A ( IL-17A) 由小鼠 CD4 T 细胞和人外周血单核细胞 (PBMC) 分泌。此外，SPH7854 强烈抑制 Th17 细胞分化并显着促进 Treg 细胞分化，同时轻微影响小鼠 CD4 T 细胞的 Th1 细胞分化。药代动力学 (PK) 研究表明，SPH7854 仅限于肠道：大鼠口服给药 (6 mg/kg) 后，SPH7854 的生物利用度和最大血浆浓度分别为 1.24 ± 0.33 nM 和 4.92 ± 11.81 nM。引人注目的是，每天两次口服 SPH7854（5 mg/kg 和 15 mg/kg）可显着缓解大鼠 2,4,6-三硝基苯磺酸 (TNBS) 诱导的结肠炎。 SPH7854，尤其是 15 mg/kg，显着缓解大鼠结肠炎的症状并改善宏观体征和微观结构，同时降低结肠粘膜 IL-17A、IL-6、肿瘤坏死因子 α (TNFα)、单核细胞趋化蛋白-1 的水平(MCP-1) 和髓过氧化物酶 (MPO)。这些证据表明，通过肠道限制拮抗剂阻断 RORγt 活性可能是 IBD 治疗的有效且安全的治疗策略。版权所有 © 2024 作者。由 Elsevier B.V. 出版。保留所有权利。

Multiple lines of evidence suggest that Retinoic Acid Related Orphan Nuclear Receptor gamma t (RORγt) is a potent therapeutic target for inflammatory bowel disease (IBD). However, systemic blockade of RORγt easily leads to thymic lymphoma and aberrant liver function. Therefore, the development of gut-limited RORγt antagonists may lead to the development of innovative IBD therapeutics that improve safety and retain effectiveness. We discovered SPH7854, a potent and selective RORγt antagonist. The effect of SPH7854 on the differentiation of T helper 1 (Th1)/Th17/regulatory T (Treg) cells was evaluated in mouse and human primary cells. SPH7854 (2-(4-(ethylsulfonyl)phenyl)-N- (6-(2-methyl-2-(pyridin-2-yl) propanoyl)pyridin-3-yl)acetamide) dose-dependently inhibited interleukin-17A (IL-17A) secretion from mouse CD4 + T cells and human peripheral blood mononuclear cells (PBMC). Additionally, SPH7854 strongly suppressed Th17 cell differentiation and considerably promoted Treg cell differentiation while slightly affected Th1 cell differentiation from mouse CD4 + T cells. The pharmacokinetic (PK) studies indicated that SPH7854 was restricted to the gut: the bioavailability and maximal plasma concentration of SPH7854 after oral administration (6 mg/kg) were 1.24 ± 0.33 % and 4.92 ± 11.81 nM, respectively, in rats. Strikingly, oral administration of SPH7854 (5 mg/kg and 15 mg/kg) twice daily significantly alleviated 2, 4, 6-trinitrobenzensulfonic acid (TNBS)-induced colitis in rats. SPH7854, especially at 15 mg/kg, significantly alleviated symptoms and improved macroscopic signs and microscopic structure in rat colitis, with decreased colonic mucosal levels of IL-17A, IL-6, tumor necrosis factor α (TNFα), monocyte chemoattractant protein-1 (MCP-1) and myeloperoxidase (MPO). These evidences indicated that blockade of RORγt activity via a gut-limited antagonist may be an effective and safe therapeutic strategy for IBD treatment.Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.