title: Acetylenic TACE inhibitors. Part 2: SAR of six-membered cyclic sulfonamide hydroxamates.
abstract: The SAR of a series of potent sulfonamide hydroxamate TACE inhibitors bearing a butynyloxy P1' group was explored. In particular, compound 5k has excellent in vitro potency against TACE enzyme and in cells, and oral activity in an in vivo model of TNF-alpha production and a collagen-induced arthritis model.
authors.affiliation: Wyeth Research, 401N. Middletown Road, Pearl River, NY 10965, USA. levinji@wyeth.com
authors.forename: J I
authors.initials: JI
authors.lastname: Levin
authors.forename: J M
authors.initials: JM
authors.lastname: Chen
authors.forename: L M
authors.initials: LM
authors.lastname: Laakso
authors.forename: M
authors.initials: M
authors.lastname: Du
authors.forename: X
authors.initials: X
authors.lastname: Du
authors.forename: A M
authors.initials: AM
authors.lastname: Venkatesan
authors.forename: V
authors.initials: V
authors.lastname: Sandanayaka
authors.forename: A
authors.initials: A
authors.lastname: Zask
authors.forename: J
authors.initials: J
authors.lastname: Xu
authors.forename: W
authors.initials: W
authors.lastname: Xu
authors.forename: Y
authors.initials: Y
authors.lastname: Zhang
authors.forename: J S
authors.initials: JS
authors.lastname: Skotnicki
mesh_terms: D051722:ADAM Proteins / Q000037:antagonists & inhibitors*; D000072198:ADAM17 Protein; D000818:Animals; D001682:Biological Availability; D061945:Caspase Inhibitors; D002460:Cell Line; D018360:Crystallography, X-Ray; D015853:Cysteine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D004285:Dogs; D006801:Humans; D006877:Hydroxamic Acids / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D015394:Molecular Structure; D009000:Monocytes; D051381:Rats; D013045:Species Specificity; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000187:drug effects
chemical_list: D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; D006877:Hydroxamic Acids; D008070:Lipopolysaccharides; D013449:Sulfonamides; D014409:Tumor Necrosis Factor-alpha; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human; C000606463:Adam17 protein, mouse; C000606464:Adam17 protein, rat