title: 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.
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.
authors.affiliation: Life Sciences Institute and the Department of Pathology, University of Michigan, Ann Arbor, Michigan, United States.
authors.forename: Yoshinari
authors.initials: Y
authors.lastname: Miyata
authors.forename: Xiaokai
authors.initials: X
authors.lastname: Li
authors.forename: Hsiu-Fang
authors.initials: HF
authors.lastname: Lee
authors.forename: Umesh K
authors.initials: UK
authors.lastname: Jinwal
authors.forename: Sharan R
authors.initials: SR
authors.lastname: Srinivasan
authors.forename: Sandlin P
authors.initials: SP
authors.lastname: Seguin
authors.forename: Zapporah T
authors.initials: ZT
authors.lastname: Young
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Brodsky
authors.forename: Chad A
authors.initials: CA
authors.lastname: Dickey
authors.forename: Duxin
authors.initials: D
authors.lastname: Sun
authors.forename: Jason E
authors.initials: JE
authors.lastname: Gestwicki
mesh_terms: D000818:Animals; D052160:Benzothiazoles / Q000138:chemical synthesis* / Q000378:metabolism* / Q000494:pharmacology; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism*; D002199:Capillary Permeability / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005260:Female; D018840:HSP70 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D011725:Pyridines / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D013844:Thiazoles / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D053778:Thiazolidines / Q000138:chemical synthesis* / Q000378:metabolism* / Q000494:pharmacology; D016875:tau Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism
chemical_list: D052160:Benzothiazoles; D018840:HSP70 Heat-Shock Proteins; D011725:Pyridines; D013844:Thiazoles; D053778:Thiazolidines; C585893:YM-08 compound; D016875:tau Proteins; C097880:MKT 077