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Identification of N-(5-(phenoxymethyl)-1,3,4-thiadiazol-2-yl)acetamide derivatives as novel protein tyrosine phosphatase epsilon inhibitors exhibiting anti-osteoclastic activity.
- Source :
-
Bioorganic & medicinal chemistry [Bioorg Med Chem] 2018 Oct 01; Vol. 26 (18), pp. 5204-5211. Date of Electronic Publication: 2018 Sep 19. - Publication Year :
- 2018
-
Abstract
- Cytosolic protein tyrosine phosphatase epsilon (cyt-PTPε) plays a central role in controlling differentiation and function of osteoclasts, whose overactivation causes osteoporosis. Based on our previous study reporting a number of cyt-PTPε inhibitory chemical compounds, we carried out a further and extended analysis of our compounds to examine their effects on cyt-PTPε-mediated dephosphorylation and on osteoclast organization and differentiation. Among five compounds showing target selectivity to cyt-PTPε over three other phosphatases in vitro, two compounds exhibited an inhibitory effect against the dephosphorylation of cellular Src protein, the cyt-PTPε substrate. Moreover, these two compounds caused destabilization of the podosome structure that is necessary for the bone-resorbing activity of osteoclasts, and also attenuated cellular differentiation of monocytes into osteoclasts, without affecting cell viability. Therefore, these findings not only verified anti-osteoclastic effects of our cyt-PTPε inhibitory compounds, but also showed that cyt-PTPε expressed in osteoclasts could be a putative therapeutic target worth considering.<br /> (Copyright © 2018 Elsevier Ltd. All rights reserved.)
- Subjects :
- Acetamides chemistry
Cell Differentiation drug effects
Dose-Response Relationship, Drug
Enzyme Inhibitors chemistry
Humans
Molecular Structure
Monocytes drug effects
Osteoclasts metabolism
Receptor-Like Protein Tyrosine Phosphatases, Class 4 metabolism
Structure-Activity Relationship
Thiadiazoles chemistry
Acetamides pharmacology
Enzyme Inhibitors pharmacology
Osteoclasts drug effects
Receptor-Like Protein Tyrosine Phosphatases, Class 4 antagonists & inhibitors
Thiadiazoles pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1464-3391
- Volume :
- 26
- Issue :
- 18
- Database :
- MEDLINE
- Journal :
- Bioorganic & medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 30249496
- Full Text :
- https://doi.org/10.1016/j.bmc.2018.09.022