Abstract
Identification of potent and reversible cruzipain inhibitors for the treatment of Chagas disease is described. The identified inhibitors bearing an amino nitrile warhead in P1 exhibit low nanomolar in vitro potency against cruzipain. Further SAR in P2 portion led to the identification of compounds, such as 26, that have a unique selectivity profile against other cysteine proteases and offering new opportunities for safer treatment of Chagas disease.
Copyright © 2010 Elsevier Ltd. All rights reserved.
MeSH terms
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Biphenyl Compounds / chemical synthesis
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Biphenyl Compounds / chemistry*
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Biphenyl Compounds / therapeutic use
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Cathepsins / antagonists & inhibitors
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Cathepsins / metabolism
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Chagas Disease / drug therapy*
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Cysteine Endopeptidases / chemistry*
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Cysteine Endopeptidases / metabolism
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Cysteine Proteases / chemistry
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Cysteine Proteases / metabolism
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Cysteine Proteinase Inhibitors / chemical synthesis
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Cysteine Proteinase Inhibitors / chemistry*
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Cysteine Proteinase Inhibitors / therapeutic use
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Humans
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Protozoan Proteins
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Structure-Activity Relationship
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Valine / analogs & derivatives*
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Valine / chemical synthesis
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Valine / chemistry
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Valine / therapeutic use
Substances
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Biphenyl Compounds
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Cysteine Proteinase Inhibitors
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Protozoan Proteins
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Cathepsins
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Cysteine Proteases
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Cysteine Endopeptidases
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cruzipain
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Valine