title: 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.
abstract: 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.
authors.affiliation: DuPont Pharmaceuticals Company, Experimental Station, P.O. Box 80500, Wilmington, Delaware 19880-0500, USA. chu-biao.xue@dupontpharma.com
authors.forename: C B
authors.initials: CB
authors.lastname: Xue
authors.forename: X
authors.initials: X
authors.lastname: He
authors.forename: R L
authors.initials: RL
authors.lastname: Corbett
authors.forename: J
authors.initials: J
authors.lastname: Roderick
authors.forename: Z R
authors.initials: ZR
authors.lastname: Wasserman
authors.forename: R Q
authors.initials: RQ
authors.lastname: Liu
authors.forename: B D
authors.initials: BD
authors.lastname: Jaffee
authors.forename: M B
authors.initials: MB
authors.lastname: Covington
authors.forename: M
authors.initials: M
authors.lastname: Qian
authors.forename: J M
authors.initials: JM
authors.lastname: Trzaskos
authors.forename: R C
authors.initials: RC
authors.lastname: Newton
authors.forename: R L
authors.initials: RL
authors.lastname: Magolda
authors.forename: R R
authors.initials: RR
authors.lastname: Wexler
authors.forename: C P
authors.initials: CP
authors.lastname: Decicco
mesh_terms: 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
chemical_list: 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