Abstract
Structure activity relationship (SAR) investigation of an oxadiazole based series led to the discovery of several potent FLAP inhibitors. Lead optimization focused on achieving functional activity while improving physiochemical properties and reducing hERG inhibition. Several compounds with favorable in vitro and in vivo properties were identified that were suitable for advanced profiling.
Keywords:
5-Lipoxygenase activating protein; Cardiovascular diseases; FLAP; Leukotrienes; Oxadiazole; Solubility; hERG.
Copyright © 2017 Elsevier Ltd. All rights reserved.
MeSH terms
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5-Lipoxygenase-Activating Protein Inhibitors / chemistry*
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5-Lipoxygenase-Activating Protein Inhibitors / metabolism
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5-Lipoxygenase-Activating Proteins / chemistry
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5-Lipoxygenase-Activating Proteins / metabolism*
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Animals
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Drug Evaluation, Preclinical
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ERG1 Potassium Channel / antagonists & inhibitors
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ERG1 Potassium Channel / metabolism
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Half-Life
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Humans
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Inhibitory Concentration 50
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Male
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Microsomes, Liver / metabolism
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Oxadiazoles / chemistry*
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Oxadiazoles / metabolism
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Rats
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Rats, Sprague-Dawley
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Rats, Wistar
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Solubility
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Structure-Activity Relationship
Substances
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5-Lipoxygenase-Activating Protein Inhibitors
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5-Lipoxygenase-Activating Proteins
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ALOX5AP protein, human
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ERG1 Potassium Channel
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KCNH2 protein, human
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Oxadiazoles