Discovery of novel and potent sulfonamide derivatives as orally available drug for psoriasis

IF 4.5 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic Chemistry Pub Date : 2024-10-05 DOI:10.1016/j.bioorg.2024.107853

Liang Qi, Yi-Nuo Ping, Shang-Shang Sun, Ran Xu, Xin-Ru Zhou

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引用次数: 0

Abstract

The retinoid-related orphan receptor gamma-t (RORγt), a member of the nuclear receptor superfamily, functions as a ligand-dependent transcription factor. As a pivotal modulator in the development and functionality of T-helper 17 (Th17) cells, RORγt plays a crucial role in immune response regulation. Inverse agonists targeting RORγt demonstrate significant potential in modulating Th17 cell activity, offering a promising avenue for the development of therapeutics aimed at treating autoimmune diseases associated with Th17 dysregulation. GSK2981278 is a potent RORγt inverse agonist, but a drawback of GSK2981278 is its low pharmacokinetic profile, leading to a clinical failure. We have explored detailed structure–activity relationship of GSK2981278 trying to improve metabolic stability while maintaining RORγt activity. As a result, a novel series of sulfonamide derivatives was discovered as potent RORγt inverse agonists with improved drug-like properties. b14 had greatly improved In Vitro metabolic stability (T_1/2 = 36.2 min) compared to GSK2981278 (T_1/2 = 0.8 min). Oral dosing of compound b14 resulted in a dose-dependent suppression of IL-17A cytokine levels within a murine model of imiquimod-induced skin inflammation, underscoring its potential as a therapeutic intervention.

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发现新型强效磺酰胺衍生物作为治疗牛皮癣的口服药物

视黄醇相关孤儿受体γ-t（RORγt）是核受体超家族的成员之一，具有配体依赖性转录因子的功能。作为 Thelper 17（Th17）细胞发育和功能的关键调节因子，RORγt 在免疫反应调节中发挥着至关重要的作用。靶向 RORγt 的反向激动剂在调节 Th17 细胞活性方面表现出巨大的潜力，为开发治疗与 Th17 失调相关的自身免疫性疾病的疗法提供了广阔的前景。GSK2981278 是一种强效的 RORγt 反激动剂，但 GSK2981278 的缺点是药代动力学特征较低，导致临床治疗失败。我们对 GSK2981278 的详细结构-活性关系进行了研究，试图在保持 RORγt 活性的同时提高其代谢稳定性。与 GSK2981278（T1/2 = 0.8 分钟）相比，b14 大大提高了体外代谢稳定性（T1/2 = 36.2 分钟）。在咪喹莫特诱导的小鼠皮肤炎症模型中，口服化合物 b14 可导致 IL-17A 细胞因子水平的剂量依赖性抑制，这突出了其作为治疗干预的潜力。

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来源期刊

Bioorganic Chemistry 生物-生化与分子生物学

CiteScore

9.70

自引率

3.90%

发文量

679

审稿时长

31 days

期刊介绍： Bioorganic Chemistry publishes research that addresses biological questions at the molecular level, using organic chemistry and principles of physical organic chemistry. The scope of the journal covers a range of topics at the organic chemistry-biology interface, including: enzyme catalysis, biotransformation and enzyme inhibition; nucleic acids chemistry; medicinal chemistry; natural product chemistry, natural product synthesis and natural product biosynthesis; antimicrobial agents; lipid and peptide chemistry; biophysical chemistry; biological probes; bio-orthogonal chemistry and biomimetic chemistry. For manuscripts dealing with synthetic bioactive compounds, the Journal requires that the molecular target of the compounds described must be known, and must be demonstrated experimentally in the manuscript. For studies involving natural products, if the molecular target is unknown, some data beyond simple cell-based toxicity studies to provide insight into the mechanism of action is required. Studies supported by molecular docking are welcome, but must be supported by experimental data. The Journal does not consider manuscripts that are purely theoretical or computational in nature. The Journal publishes regular articles, short communications and reviews. Reviews are normally invited by Editors or Editorial Board members. Authors of unsolicited reviews should first contact an Editor or Editorial Board member to determine whether the proposed article is within the scope of the Journal.