Abstract
The structure-activity relationship studies of a novel sulfonylurea series of piperazine pyridazine-based small molecule glucan synthase inhibitors is described. The optimization of PK profiles within the series led to the discovery of several compounds with improved pharmacokinetic profiles which demonstrated in vitro potency against clinically relevant strains. However, the advancement of compounds from this series into a non-lethal systemic fungal infection model failed to show in vivo efficacy.
Copyright © 2012 Elsevier Ltd. All rights reserved.
MeSH terms
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Animals
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Antifungal Agents / chemistry*
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Antifungal Agents / pharmacology
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Candida / drug effects
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Cell Line
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Enzyme Inhibitors / chemistry*
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Enzyme Inhibitors / pharmacology
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Glucosyltransferases / antagonists & inhibitors*
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Humans
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Lead / chemistry*
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Molecular Structure
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Piperazine
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Piperazines / chemistry*
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Pyridazines / chemistry*
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Pyridazines / pharmacology
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Rats
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Structure-Activity Relationship
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Sulfonylurea Compounds / chemistry*
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Sulfonylurea Compounds / pharmacology
Substances
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Antifungal Agents
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Enzyme Inhibitors
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Piperazines
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Pyridazines
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Sulfonylurea Compounds
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Piperazine
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Lead
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pyridazine
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Glucosyltransferases
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glucan synthase