Abstract
We report the discovery and characterization of a series of benzoisothiazolone inhibitors of PHOSPHO1, a newly identified soluble phosphatase implicated in skeletal mineralization and soft tissue ossification abnormalities. High-throughput screening (HTS) of a small molecule library led to the identification of benzoisothiazolones as potent and selective inhibitors of PHOSPHO1. Critical structural requirements for activity were determined, and the compounds were subsequently derivatized and measured for in vitro activity and ADME parameters including metabolic stability and permeability. On the basis of its overall profile the benzoisothiazolone analogue 2q was selected as MLPCN probe ML086.
Keywords:
ML086; PHOSPHO1; Phosphatase; Probe compound; Vascular calcification.
Copyright © 2014 Elsevier Ltd. All rights reserved.
Publication types
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Research Support, American Recovery and Reinvestment Act
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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Benzamides / chemical synthesis
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Benzamides / chemistry
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Benzamides / pharmacology*
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Benzothiazoles / chemical synthesis
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Benzothiazoles / chemistry
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Benzothiazoles / pharmacology*
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Dose-Response Relationship, Drug
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Drug Design*
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Enzyme Inhibitors / chemical synthesis
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Enzyme Inhibitors / chemistry
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Enzyme Inhibitors / pharmacology*
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Hepatocytes / drug effects
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High-Throughput Screening Assays
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Humans
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Hydrogen-Ion Concentration
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Mice
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Molecular Structure
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Phosphoric Monoester Hydrolases / antagonists & inhibitors*
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Phosphoric Monoester Hydrolases / metabolism
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Small Molecule Libraries / chemical synthesis
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Small Molecule Libraries / chemistry
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Small Molecule Libraries / pharmacology*
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Structure-Activity Relationship
Substances
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Benzamides
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Benzothiazoles
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Enzyme Inhibitors
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ML086 compound
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Small Molecule Libraries
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PHOSPHO1 protein, human
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Phosphoric Monoester Hydrolases