Abstract
We report a series of inhibitors of secreted phospholipases A2 (sPLA2s) based on substituted indoles, 6,7-benzoindoles, and indolizines derived from LY315920, a well-known indole-based sPLA2 inhibitor. Using the human group X sPLA2 crystal structure, we prepared a highly potent and selective indole-based inhibitor of this enzyme. Also, we report human and mouse group IIA and IIE specific inhibitors and a substituted 6,7-benzoindole that inhibits nearly all human and mouse sPLA2s in the low nanomolar range.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Enzyme Inhibitors / chemical synthesis*
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Enzyme Inhibitors / chemistry
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Enzyme Inhibitors / pharmacology*
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Humans
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Indoles / chemistry
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Indoles / pharmacology
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Indolizidines / chemistry
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Indolizidines / pharmacology
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Mice
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Models, Molecular
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Molecular Structure
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Phospholipases A2, Secretory / antagonists & inhibitors*
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Phospholipases A2, Secretory / chemistry
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Phospholipases A2, Secretory / metabolism
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Sensitivity and Specificity
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Structure-Activity Relationship
Substances
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Enzyme Inhibitors
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Indoles
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Indolizidines
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Phospholipases A2, Secretory