First-in-Class Hydrazide-Based HDAC6 Selective Inhibitor with Potent Oral Anti-Inflammatory Activity by Attenuating NLRP3 Inflammasome Activation,Journal of Medicinal Chemistry

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First-in-Class Hydrazide-Based HDAC6 Selective Inhibitor with Potent Oral Anti-Inflammatory Activity by Attenuating NLRP3 Inflammasome Activation
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2022-09-08 , DOI: 10.1021/acs.jmedchem.2c00853
Kairui Yue ₁ , Simin Sun ₁ , Geng Jia ₁ , Mengting Qin ₁ , Xiaohan Hou ₁ , C James Chou ₂ , Chao Huang ₁ , Xiaoyang Li _{1,

3}

Affiliation

In this study, we report the first highly selective HDAC6 inhibitor with hydrazide as the zinc-binding group (ZBG), which displays superior pharmacokinetic properties to the current hydroxamic acid inhibitors. Structure–activity relationship study reveals that ethyl group substituent hydrazide-based ZBG and cap group with more substantial rigidity and larger volume increase the HDAC6 selectivity of designed compounds. Representative inhibitor 35m exhibits potent HDAC6 inhibitory activity with an IC₅₀ value of 0.019 μM. To our surprise, 35m establishes significant improvement in the pharmacokinetic property with much higher AUC_0-inf (10292 ng·h/mL) and oral bioavailability (93.4%) than hydroximic acid-based HDAC6 inhibitors Tubastatin A and ACY-1215. Low-dose 35m remarkably decreases LPS-induced IL-1β release both in vitro and in vivo by blocking the activation of NLRP3, indicating that 35m can be a potential orally active therapeutic agent for the treatment of NLRP3-related diseases.

中文翻译：

一流的基于酰肼的 HDAC6 选择性抑制剂，通过减弱 NLRP3 炎性体激活而具有有效的口服抗炎活性

在这项研究中，我们报告了第一个以酰肼为锌结合基团 (ZBG) 的高选择性 HDAC6 抑制剂，与目前的异羟肟酸抑制剂相比，它表现出优越的药代动力学特性。构效关系研究表明，乙基取代基酰肼基 ZBG 和具有更大刚性和更大体积的帽基增加了设计化合物的 HDAC6 选择性。代表性抑制剂35m表现出有效的 HDAC6 抑制活性，IC ₅₀值为 0.019 μM。令我们惊讶的是，35m显着改善了药代动力学特性，AUC _0-inf更高(10292 ng·h/mL) 和口服生物利用度 (93.4%) 优于基于羟肟酸的 HDAC6 抑制剂 Tubastatin A 和 ACY-1215。低剂量35m通过阻断 NLRP3 的激活显着降低 LPS 诱导的 IL-1β在体外和体内的释放，表明35m可以成为治疗 NLRP3 相关疾病的潜在口服活性治疗剂。

更新日期：2022-09-08

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