Abstract
Class I phosphoinositide 3-kinases (PI3Ks), particularly PI3Kγ, have become attractive drug targets for inflammatory and autoimmune disorders such as rheumatoid arthritis. Herein, we describe the synthesis and the structure-activity relationships (SAR) of a series of 2-amino-5-oxadiazolyl thiazoles, culminating in the identification of 8j (TASP0415914), an orally potent inhibitor of phosphoinositide 3-kinase γ (PI3Kγ). TASP0415914 demonstrated good potency in a cell-based assay and, furthermore, exhibited in vivo efficacy in a collagen induced arthritis (CIA) model in mice after oral administration.
Keywords:
2-Amino-5-oxadiazolyl thiazole; Collagen induced arthritis (CIA) model; Phosphoinositide 3-kinase γ; The Ames test.
Copyright © 2013 Elsevier Ltd. All rights reserved.
MeSH terms
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Administration, Oral
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Animals
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Arthritis, Experimental / chemically induced
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Arthritis, Experimental / drug therapy*
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Arthritis, Experimental / enzymology
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Class Ib Phosphatidylinositol 3-Kinase / metabolism
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Collagen
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Disease Models, Animal
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Dose-Response Relationship, Drug
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Drug Discovery*
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Enzyme Inhibitors / administration & dosage
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Enzyme Inhibitors / chemistry
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Enzyme Inhibitors / pharmacology*
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Male
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Mice
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Mice, Inbred DBA
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Molecular Structure
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Oxadiazoles / administration & dosage
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Oxadiazoles / chemistry
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Oxadiazoles / pharmacology*
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Phosphoinositide-3 Kinase Inhibitors*
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Structure-Activity Relationship
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Thiazoles / administration & dosage
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Thiazoles / chemistry
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Thiazoles / pharmacology*
Substances
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Enzyme Inhibitors
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N-(5-(3-(3-hydroxypiperidin-1-yl)-1,2,4-oxadiazol-5-yl)-4-methyl-1,3-thiazol-2-yl)acetamide
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Oxadiazoles
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Phosphoinositide-3 Kinase Inhibitors
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Thiazoles
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Collagen
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Class Ib Phosphatidylinositol 3-Kinase
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Pik3cg protein, mouse