Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266071, China.
Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, Medical University of South Carolina, Charleston, South Carolina 29425, United States.
J Med Chem. 2022 Sep 22;65(18):12140-12162. doi: 10.1021/acs.jmedchem.2c00853. Epub 2022 Sep 8.
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 exhibits potent HDAC6 inhibitory activity with an IC value of 0.019 μM. To our surprise, establishes significant improvement in the pharmacokinetic property with much higher AUC (10292 ng·h/mL) and oral bioavailability (93.4%) than hydroximic acid-based HDAC6 inhibitors Tubastatin A and ACY-1215. Low-dose remarkably decreases LPS-induced IL-1β release both and by blocking the activation of NLRP3, indicating that can be a potential orally active therapeutic agent for the treatment of NLRP3-related diseases.
在这项研究中，我们报告了首个具有酰腙作为锌结合基团（ZBG）的高度选择性 HDAC6 抑制剂，其药代动力学性质优于当前的羟肟酸抑制剂。构效关系研究表明，基于乙基取代酰腙的 ZBG 和具有更大刚性和更大体积的盖帽基团增加了设计化合物对 HDAC6 的选择性。代表性抑制剂 表现出强效的 HDAC6 抑制活性，IC 值为 0.019 μM。令我们惊讶的是， 与基于羟肟酸的 HDAC6 抑制剂 Tubastatin A 和 ACY-1215 相比，在药代动力学性质方面有显著改善，AUC（10292ng·h/mL）和口服生物利用度（93.4%）更高。低剂量 可显著降低 LPS 诱导的 IL-1β 释放， 通过阻断 NLRP3 的激活，表明 可以成为一种有潜力的用于治疗 NLRP3 相关疾病的口服活性治疗剂。
