Charles River Discovery (previously BioFocus), Chesterford Research Park, Saffron Walden, Essex CB10 1XL, United Kingdom.
CHDI Management/CHDI Foundation Inc., 6080 Center Drive, Suite 700, Los Angeles, CA 90045, United States.
Bioorg Med Chem Lett. 2019 Jan 1;29(1):83-88. doi: 10.1016/j.bmcl.2018.11.009. Epub 2018 Nov 13.
We have identified a potent, cell permeable and CNS penetrant class IIa histone deacetylase (HDAC) inhibitor 22, with >500-fold selectivity over class I HDACs (1,2,3) and ∼150-fold selectivity over HDAC8 and the class IIb HDAC6 isoform. Dose escalation pharmacokinetic analysis demonstrated that upon oral administration, compound 22 can reach exposure levels in mouse plasma, muscle and brain in excess of cellular class IIa HDAC IC levels for ∼8 h. Given the interest in aberrant class IIa HDAC function for a number of neurodegenerative, neuromuscular, cardiac and oncology indications, compound 22 (also known as CHDI-390576) provides a selective and potent compound to query the role of class IIa HDAC biology, and the impact of class IIa catalytic site occupancy in vitro and in vivo.
我们已经鉴定出一种有效的、细胞通透性强且可穿透中枢神经系统的 IIa 类组蛋白去乙酰化酶 (HDAC) 抑制剂 22，对 I 类 HDAC（1、2、3）的选择性超过 500 倍，对 HDAC8 和 IIb 类 HDAC6 同工型的选择性超过 150 倍。剂量递增药代动力学分析表明，口服给予化合物 22 后，其在小鼠血浆、肌肉和脑中的暴露水平可超过细胞 IIa 类 HDAC IC 水平达 8 小时以上。鉴于许多神经退行性、神经肌肉、心脏和肿瘤适应症中异常 IIa 类 HDAC 功能的研究兴趣，化合物 22（也称为 CHDI-390576）提供了一种选择性和有效的化合物，可用于研究 IIa 类 HDAC 生物学的作用以及体外和体内 IIa 类催化位点占有率的影响。
