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
Document Type
Article
Publication Date
2013
Digital Object Identifier (DOI)
https://doi.org/10.1021/cn300210g
Abstract
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.
Was this content written or created while at USF?
Yes
Citation / Publisher Attribution
ACS Chemical Neuroscience, v. 4, issue 6, p. 930-939
Scholar Commons Citation
Miyata, Yoshinari; Li, Xiaokai; Lee, Hsiu-Fang; Jinwal, Umesh K.; Srinivasan, Sharan R.; Seguin, Sandlin P.; Young, Zapporah T.; Brodsky, Jeffrey L.; Dickey, Chad A.; Sun, Duxin; and Gestwicki, Jason E., "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" (2013). Molecular Medicine Faculty Publications. 101.
https://digitalcommons.usf.edu/mme_facpub/101