Novel Technology Center of Pharmaceutical Chemistry, Shanghai Institute of Pharmaceutical Industry, Shanghai, 201203, China; Shanghai Engineering Research Center of Pharmaceutical Process, Shanghai, 201203, China.
Novel Technology Center of Pharmaceutical Chemistry, Shanghai Institute of Pharmaceutical Industry, Shanghai, 201203, China; School of Pharmacy, Shanghai Jiao Tong University, Shanghai, 200240, China.
Eur J Med Chem. 2021 Jun 5;218:113383. doi: 10.1016/j.ejmech.2021.113383. Epub 2021 Mar 17.
Histone deacetylase 6 (HDAC6) has become a promising therapeutic target for central nervous system diseases due to its more complex protein structure and biological functions. However, low brain penetration of reported HDAC6 inhibitors limits its clinical application in neurological disorders. Therefore, the benzazepine, a brain-penetrant rigid fragment, was utilized to design a series of selective HDAC6 inhibitors to improve brain bioavailability. Various synthetic strategies were applied to assemble the tetrahydro-benzazepine ring, and 22 compounds were synthesized. Among them, compound 5 showed low nanomolar potency and strong isozyme selectivity for the inhibition of HDAC6 (IC = 1.8 nM, 141-fold selectivity over HDAC1) with efficient binding patterns like coordination with the zinc ion and π-π stacking effect. Western blot results showed it could efficiently transport into SH-SY5Y cells and selectively enhance the acetylation level of α-tubulin with a moderate effect on Histone H3. Notably, pharmacokinetic studies demonstrated that compound 5 (brain/plasma ratio of 2.30) had an excellent ability to penetrate the blood-brain barrier of C57 mice. In male rats with transient middle cerebral artery occlusion (MCAO), compound 5 significantly reduced the cerebral infarction from 21.22% to 11.47% and alleviated neurobehavioral deficits in post-ischemic treatment, which provided a strong rationale for pursuing HDAC6-based therapies for ischemic stroke.
组蛋白去乙酰化酶 6（HDAC6）由于其更复杂的蛋白质结构和生物学功能，已成为治疗中枢神经系统疾病的有希望的治疗靶点。然而，报道的 HDAC6 抑制剂的脑穿透性低限制了其在神经障碍中的临床应用。因此，利用苯并氮杂䓬（一种具有脑穿透性的刚性片段）来设计一系列选择性 HDAC6 抑制剂以提高脑生物利用度。应用了各种合成策略来组装四氢苯并氮杂䓬环，合成了 22 个化合物。其中，化合物 5 对 HDAC6 的抑制表现出低纳摩尔效力和强同工酶选择性（IC=1.8 nM，对 HDAC1 的选择性为 141 倍），具有与锌离子配位和π-π堆积作用等有效的结合模式。Western blot 结果表明，它可以有效地转运到 SH-SY5Y 细胞中，并选择性地增强α-微管蛋白的乙酰化水平，对组蛋白 H3 有适度的影响。值得注意的是，药代动力学研究表明，化合物 5（脑/血浆比为 2.30）具有优异的穿透 C57 小鼠血脑屏障的能力。在短暂性大脑中动脉闭塞（MCAO）的雄性大鼠中，化合物 5 可使脑梗死从 21.22%显著降低至 11.47%，并减轻缺血后治疗中的神经行为缺陷，这为基于 HDAC6 的治疗缺血性中风提供了强有力的理论依据。
