Abstract
Potent and selective inhibitors of tumor necrosis factor-alpha converting enzyme (TACE) were discovered with several new heterocyclic P1' groups in conjunction with cyclic beta-amino hydroxamic acid scaffolds. Among them, the pyrazolopyridine provided the best overall profile when combined with tetrahydropyran beta-amino hydroxamic acid scaffold. Specifically, inhibitor 49 showed IC(50) value of 1 nM against porcine TACE and 170 nM in the suppression of LPS-induced TNF-alpha of human whole blood. Compound 49 also displayed excellent selectivity over a wide panel of MMPs as well as excellent oral bioavailability (F%>90%) in rat n-in-1 PK studies.
MeSH terms
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ADAM Proteins / antagonists & inhibitors*
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ADAM Proteins / metabolism
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ADAM17 Protein
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Administration, Oral
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Animals
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Benzofurans / chemistry*
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Biological Availability
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Humans
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Hydroxamic Acids / chemistry
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Imidazoles / chemistry*
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Indoles / chemistry*
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Lipopolysaccharides / pharmacology
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Matrix Metalloproteinase Inhibitors
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Molecular Structure
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Protease Inhibitors / chemical synthesis
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Protease Inhibitors / pharmacokinetics
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Protease Inhibitors / pharmacology*
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Pyrazoles / chemistry*
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Pyridines / chemistry*
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Rats
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Rats, Sprague-Dawley
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Structure-Activity Relationship
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Tumor Necrosis Factor-alpha / metabolism
Substances
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Benzofurans
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Hydroxamic Acids
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Imidazoles
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Indoles
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Lipopolysaccharides
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Matrix Metalloproteinase Inhibitors
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Protease Inhibitors
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Pyrazoles
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Pyridines
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Tumor Necrosis Factor-alpha
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pyrazolopyridine
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indole
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ADAM Proteins
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ADAM17 Protein
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ADAM17 protein, human
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Adam17 protein, rat
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benzofuran