Abstract
Using a pyrimidine-2,4,6-trione motif as a zinc-binding group, a series of selective inhibitors of tumor necrosis factor-alpha converting enzyme (TACE) was discovered. Optimization of initial lead 1 resulted in a potent inhibitor (51), with an IC(50) of 2 nM in a porcine TACE assay. To the best of our knowledge, compound 51 and related analogues represent first examples of non-hydroxamate-based inhibitors of TACE with single digit nanomolar potency.
MeSH terms
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ADAM Proteins / antagonists & inhibitors*
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ADAM17 Protein
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Barbiturates / chemical synthesis
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Barbiturates / chemistry*
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Barbiturates / pharmacology*
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Benzamides / chemical synthesis
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Benzamides / chemistry*
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Benzamides / pharmacology*
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Hydroxamic Acids / chemistry
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Inhibitory Concentration 50
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Protease Inhibitors / chemical synthesis
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Protease Inhibitors / chemistry*
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Protease Inhibitors / pharmacology*
Substances
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Barbiturates
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Benzamides
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Hydroxamic Acids
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N-(4-(methanesulfonylpiperazin-1-yl)-2,4,6-trioxopyrimidin-4-ylmethyl)-4-((2-methylquinolin-4-yl)methoxy)benzamide
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Protease Inhibitors
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ADAM Proteins
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ADAM17 Protein