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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Benzothiazoles / chemical synthesis*
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Benzothiazoles / metabolism*
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Benzothiazoles / pharmacology
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Blood-Brain Barrier / drug effects
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Blood-Brain Barrier / metabolism*
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Capillary Permeability / drug effects
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Capillary Permeability / physiology*
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Cells, Cultured
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Drug Evaluation, Preclinical / methods
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Female
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HSP70 Heat-Shock Proteins / antagonists & inhibitors*
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HSP70 Heat-Shock Proteins / chemistry
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HSP70 Heat-Shock Proteins / metabolism*
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Humans
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MCF-7 Cells
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Mice
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Microsomes, Liver / drug effects
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Microsomes, Liver / metabolism
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Pyridines / chemistry
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Pyridines / metabolism*
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Pyridines / pharmacology
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Thiazoles / chemistry
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Thiazoles / metabolism*
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Thiazoles / pharmacology
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Thiazolidines / chemical synthesis*
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Thiazolidines / metabolism*
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Thiazolidines / pharmacology
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tau Proteins / antagonists & inhibitors*
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tau Proteins / chemistry
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tau Proteins / metabolism
Substances
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Benzothiazoles
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HSP70 Heat-Shock Proteins
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Pyridines
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Thiazoles
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Thiazolidines
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YM-08 compound
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tau Proteins
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MKT 077