The synthesis and bioactivities of ROCK2 inhibitors with 1,2-dithiolan-3-yl motif

IF 4.1 4区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

RSC medicinal chemistry Pub Date : 2024-08-01 DOI:10.1039/d4md00438h

Ruolin Cao, Fangyu Du, Zhiqiang Liu, Pengcheng Cai, Minggang Qi, Wei Xiao, Xuefei Bao, Guoliang Chen

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Abstract

Rho-associated coiled-coil containing kinase (ROCK) plays an important role in inflammation. Herein, a series of compounds were designed and synthesized as ROCK inhibitors based on the structure-based drug design (SBDD) strategy and were evaluated for cytotoxicity, antioxidant activity and anti-inflammatory activity. Among them, compound DC24 was identified as the optimal hit in enzymatic screening with an IC₅₀ value of 0.124 μM against ROCK2 and 50-fold selectivity over ROCK1. DC24 has a novel lipid amide scaffold with a bis(4-fluorophenyl)methyl substituent, and DC24 is the first ROCK2 inhibitor interacting with the hinge region of ROCK2 via the 1,2-dithiolan-3-yl motif, which has been confirmed by the binding model of DC24 with ROCK2. In a complete Freund's adjuvant (CFA) induced acute inflammation model, DC24 at a dose of 5 mg kg⁻¹ exhibited an anti-inflammatory effect better than that of belumosudil. Furthermore, DC24 exhibits good safety in vivo.

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具有 1,2-二硫环戊-3-基基团的 ROCK2 抑制剂的合成及其生物活性

Rho相关含盘卷激酶（ROCK）在炎症中发挥着重要作用。本文基于基于结构的药物设计（SBDD）策略，设计合成了一系列化合物作为ROCK抑制剂，并对其细胞毒性、抗氧化活性和抗炎活性进行了评价。其中，化合物 DC24 在酶筛选中被确定为最佳靶点，其对 ROCK2 的 IC50 值为 0.124 μM，选择性是 ROCK1 的 50 倍。DC24 具有双（4-氟苯基）甲基取代基的新型脂质酰胺支架，是首个通过 1,2-二硫环戊-3-基基团与 ROCK2 铰链区相互作用的 ROCK2 抑制剂，DC24 与 ROCK2 的结合模型证实了这一点。在完全弗氏佐剂（CFA）诱导的急性炎症模型中，剂量为 5 mg kg-1 的 DC24 的抗炎效果优于贝卢莫司地。此外，DC24 在体内表现出良好的安全性。

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来源期刊

RSC medicinal chemistry Multiple-

CiteScore

5.80

自引率

2.40%

发文量

129