Abstract
Isothiazolo[4,3-b]pyridines have been extensively explored as inhibitors of cyclin G-associated kinase (GAK). In order to expand the structure-activity relationship study and to discover other chemotypes that act as GAK inhibitors, the closely related isothiazolo[4,5-b]pyridine scaffold was explored. An easy and efficient synthetic procedure to access 3,5- and 3,6-dihalogenated isothiazolo[4,5-b]pyridines as key building blocks was developed. Regioselective functionalization with various substituents was performed. None of the newly synthesized isothiazolo[4,5-b]pyridines were active as GAK inhibitors. Molecular modeling was applied to rationalise their inactivity as GAK binders.
Publication types
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Research Support, U.S. Gov't, P.H.S.
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Research Support, Non-U.S. Gov't
MeSH terms
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Humans
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Intracellular Signaling Peptides and Proteins
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Models, Molecular
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Molecular Structure
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Protein Kinase Inhibitors* / chemical synthesis
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Protein Kinase Inhibitors* / chemistry
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Protein Kinase Inhibitors* / pharmacology
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Protein Serine-Threonine Kinases / antagonists & inhibitors
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Protein Serine-Threonine Kinases / metabolism
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Pyridines* / chemical synthesis
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Pyridines* / chemistry
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Pyridines* / pharmacology
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Structure-Activity Relationship
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Thiazoles* / chemical synthesis
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Thiazoles* / chemistry
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Thiazoles* / pharmacology
Substances
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Protein Kinase Inhibitors
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Pyridines
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Thiazoles
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GAK protein, human
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Protein Serine-Threonine Kinases
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Intracellular Signaling Peptides and Proteins