Discovery of macrocyclic hydroxamic acids containing biphenylmethyl derivatives at P1', a series of selective TNF-alpha converting enzyme inhibitors with potent cellular activity in the inhibition of TNF-alpha release.
SAR exploration at P1' using an anti-succinate-based macrocyclic hydroxamic acid as a template led to the identification of several bulky biphenylmethyl P1' derivatives which confer potent porcine TACE and anti-TNF-alpha cellular activities with high selectivity versus most of the MMPs screened. Our studies demonstrate for the first time that TACE has a larger S1' pocket in comparison to MMPs and that potent and selective TACE inhibitors can be achieved by incorporation of sterically bulky P1' residues.
Xue
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DuPont Pharmaceuticals Company, Experimental Station, P.O. Box 80500, Wilmington, Delaware 19880-0500, USA. chu-biao.xue@dupontpharma.com
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Corbett
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Roderick
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Wasserman
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Liu
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Jaffee
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Covington
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Qian
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Trzaskos
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Newton
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Magolda
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Wexler
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Decicco
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D051722:ADAM Proteins; D000072198:ADAM17 Protein; D001665:Binding Sites; D006573:Heterocyclic Compounds, 1-Ring / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D006877:Hydroxamic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors*; D008958:Models, Molecular; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011485:Protein Binding; D013329:Structure-Activity Relationship; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000378:metabolism
C438587:2,11-diaza--4-(2-(trifluoromethyl)phenyl)-5-(hydroxyaminocarbonyl)-1-((((piperazin-1-yl)carbonyl)methyl)aminocarbonyl)-9-oxa-3,10-dioxocyclopentadecane; C438586:2,11-diaza-4-(2-(trifluoromethyl)phenyl)-5-(hydroxyaminocarbonyl)-1-((((morpholin-4-yl)carbonyl)methyl)aminocarbonyl)-9-oxa-3,10-dioxocyclopentadecane; D006573:Heterocyclic Compounds, 1-Ring; D006877:Hydroxamic Acids; D008070:Lipopolysaccharides; D011480:Protease Inhibitors; D014409:Tumor Necrosis Factor-alpha; D051722:ADAM Proteins; D008666:Metalloendopeptidases; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human