title: Discovery of selective hydroxamic acid inhibitors of tumor necrosis factor-alpha converting enzyme.
abstract: Modification of the P(1)' substituent of macrocyclic matrix metalloproteinase (MMP) inhibitors provided compounds that are selective for inhibition of tumor necrosis factor-alpha converting enzyme (TACE) over MMP-1 and MMP-2. Several analogues potently inhibited the release of TNF-alpha in a THP-1 cellular assay. Compounds containing a trimethoxyphenyl group in the P(1)' substituent demonstrated TACE selectivity across several series of hydroxamate-based inhibitors.
authors.affiliation: Cancer Research Area, Abbott Laboratories, Dept. 47J, Bldg. AP10, 100 Abbott Park Road, Abbott Park, IL 60064, USA. james.holms@abbott.com
authors.forename: J
authors.initials: J
authors.lastname: Holms
authors.forename: K
authors.initials: K
authors.lastname: Mast
authors.forename: P
authors.initials: P
authors.lastname: Marcotte
authors.forename: I
authors.initials: I
authors.lastname: Elmore
authors.forename: J
authors.initials: J
authors.lastname: Li
authors.forename: L
authors.initials: L
authors.lastname: Pease
authors.forename: K
authors.initials: K
authors.lastname: Glaser
authors.forename: D
authors.initials: D
authors.lastname: Morgan
authors.forename: M
authors.initials: M
authors.lastname: Michaelides
authors.forename: S
authors.initials: S
authors.lastname: Davidsen
mesh_terms: D051722:ADAM Proteins; D000072198:ADAM17 Protein; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D006877:Hydroxamic Acids / Q000138:chemical synthesis* / Q000494:pharmacology; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D006877:Hydroxamic Acids; D014409:Tumor Necrosis Factor-alpha; D051722:ADAM Proteins; D008666:Metalloendopeptidases; D000072198:ADAM17 Protein