Synthesis and Initial Evaluation of YM-08, a Blood-Brain Barrier Permeable Derivative of the Heat Shock Protein 70 (Hsp70) Inhibitor MKT-077, Which Reduces Tau Levels
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- 作者：Yoshinari Miyata ; Xiaokai Li ; Hsiu-Fang Lee ; Umesh K. Jinwal ; Sharan R. Srinivasan ; Sandlin P. Seguin ; Zapporah T. Young ; Jeffrey L. Brodsky ; Chad A. Dickey ; Duxin Sun ; Jason E. Gestwicki
- 刊名：ACS Chemical Neuroscience
- 出版年：2013
- 出版时间：June 19, 2013
- 年：2013
- 卷：4
- 期：6
- 页码：930-939
- 全文大小：613K
- 年卷期：v.4,no.6(June 19, 2013)
- ISSN：1948-7193
文摘
The molecular chaperone, heat shock protein 70 (Hsp70), is an emerging drug target for treating neurodegenerative tauopathies. We recently found that one promising Hsp70 inhibitor, MKT-077, reduces tau levels in cellular models. However, MKT-077 does not penetrate the blood-brain barrier (BBB), limiting its use as either a clinical candidate or probe for exploring Hsp70 as a drug target in the central nervous system (CNS). We hypothesized that replacing the cationic pyridinium moiety in MKT-077 with a neutral pyridine might improve its clogP and enhance its BBB penetrance. To test this idea, we designed and synthesized YM-08, a neutral analogue of MKT-077. Like the parent compound, YM-08 bound to Hsp70 in vitro and reduced phosphorylated tau levels in cultured brain slices. Pharmacokinetic evaluation in CD1 mice showed that YM-08 crossed the BBB and maintained a brain/plasma (B/P) value of 0.25 for at least 18 h. Together, these studies suggest that YM-08 is a promising scaffold for the development of Hsp70 inhibitors suitable for use in the CNS.