当前位置: X-MOL 学术Bioorg. Med. Chem. Lett. › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
Development and characterization of a CNS-penetrant benzhydryl hydroxamic acid class IIa histone deacetylase inhibitor
Bioorganic & Medicinal Chemistry Letters ( IF 2.7 ) Pub Date : 2018-11-13 , DOI: 10.1016/j.bmcl.2018.11.009
Christopher A. Luckhurst , Omar Aziz , Vahri Beaumont , Roland W. Bürli , Perla Breccia , Michel C. Maillard , Alan F. Haughan , Marieke Lamers , Phil Leonard , Kim L. Matthews , Gilles Raphy , Andrew J. Stott , Ignacio Munoz-Sanjuan , Beth Thomas , Michael Wall , Grant Wishart , Dawn Yates , Celia Dominguez

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 IC50 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.



中文翻译:

中枢神经系统渗透性二苯甲基异羟肟酸IIa类组蛋白脱乙酰基酶抑制剂的开发与表征

我们已经确定了一种有效的,细胞可渗透的CNS渗透性IIa类组蛋白脱乙酰基酶(HDAC)抑制剂22,其选择性是I类HDAC(1,2,3)的> 500倍,选择性是HDAC8和IIb类的〜150倍HDAC6同工型。剂量递增的药代动力学分析表明,口服时,化合物22在小鼠血浆,肌肉和大脑中的暴露水平可以超过细胞IIa类HDAC IC 50的水平,持续约8小时。鉴于人们对IIa类HDAC异常功能对于多种神经退行性,神经肌肉,心脏和肿瘤学适应症的兴趣,化合物22(也称为CHDI-390576)提供了一种选择性和有效的化合物,可查询IIa类HDAC生物学的作用以及IIa类催化位点在体外体内占有的影响。

更新日期:2018-11-13
down
wechat
bug