Abstract
Previously disclosed TAFIa inhibitors having a urea zinc-binding motif were used as the starting point for the development of a novel class of highly potent inhibitors having a sulfamide zinc-binding motif. High-resolution X-ray cocrystal structures were used to optimize the structures and reveal a highly unusual sulfamide configuration. A selected sulfamide was profiled in vitro and in vivo and displayed a promising ADMET profile.
MeSH terms
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Animals
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Carboxypeptidase B2 / antagonists & inhibitors*
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Carboxypeptidase B2 / metabolism
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Crystallography, X-Ray
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Dose-Response Relationship, Drug
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Humans
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Mice
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Microsomes / chemistry
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Microsomes / metabolism
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Models, Molecular
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Molecular Structure
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Protease Inhibitors / chemical synthesis
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Protease Inhibitors / chemistry*
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Protease Inhibitors / pharmacology*
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Rats
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Small Molecule Libraries / chemical synthesis
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Small Molecule Libraries / chemistry*
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Small Molecule Libraries / pharmacology*
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Structure-Activity Relationship
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Sulfonamides / chemistry
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Sulfonamides / pharmacology*
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Zinc / chemistry*
Substances
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Protease Inhibitors
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Small Molecule Libraries
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Sulfonamides
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Carboxypeptidase B2
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Zinc