title: Characterization of (2R, 3S)-2-([[4-(2-butynyloxy)phenyl]sulfonyl]amino)-N,3-dihydroxybutanamide, a potent and selective inhibitor of TNF-alpha converting enzyme.
abstract: TNF-alpha converting enzyme (TACE) is a validated therapeutic target for the development of oral tumor necrosis factor-alpha (TNF-alpha) inhibitors. Here we report the pre-clinical results and characterization of a selective and potent TACE inhibitor, (2R, 3S)-2-([[4-(2-butynyloxy)phenyl]sulfonyl]amino)-N,3-dihydroxybutanamide (TMI-2), in various in vitro and in vivo assays. TMI-2 is a potent TACE inhibitor in an enzymatic FRET assay (IC50=2 nM). It is more than 250-fold selective over MMP-1, -7, -9, -14, and ADAM-10 in vitro. In cell-based assays and human whole blood, TMI-2 inhibits lipopolysaccharide (LPS)-induced TNF secretion with IC50s<1 uM. Importantly, TMI-2 inhibits the spontaneous release of TNF-alpha in human synovium tissue explants of rheumatoid arthritis patients with an IC50 of 0.8 microM. In vivo, TMI-2 potently inhibits LPS-induced TNF-alpha production in mice (ED50=3 mg/kg). In the adjuvant-induced arthritis (AIA) model in rats, treatment with TMI-2 at 30 mg/kg and 100 mg/kg p.o. b.i.d. was highly effective in reducing joint arthritis scores. In a semi-therapeutic collagen-induced arthritis (CIA) model in mice, TMI-2 is highly effective in reducing disease severity scores after oral treatment at 100 mg/kg twice per day. In summary, TMI-2 is a potent and selective TACE inhibitor that inhibits TNF-alpha production and reduces the arthritis scores in pre-clinical models. TMI-2 represents a novel class of TACE inhibitors that may be effective and beneficial in the treatment of rheumatoid arthritis as well as other TNF-mediated inflammatory autoimmune diseases.
authors.affiliation: Department of Inflammation, Wyeth Research, 200 Cambridge Park Drive, Cambridge, MA 02140, USA. yzhang@wyeth.com
authors.forename: Yuhua
authors.initials: Y
authors.lastname: Zhang
authors.forename: Martin
authors.initials: M
authors.lastname: Hegen
authors.forename: Jun
authors.initials: J
authors.lastname: Xu
authors.forename: James C
authors.initials: JC
authors.lastname: Keith
authors.forename: Guixian
authors.initials: G
authors.lastname: Jin
authors.forename: Xuemei
authors.initials: X
authors.lastname: Du
authors.forename: Terri
authors.initials: T
authors.lastname: Cummons
authors.forename: Barbara J
authors.initials: BJ
authors.lastname: Sheppard
authors.forename: LinHong
authors.initials: L
authors.lastname: Sun
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhu
authors.forename: Vikram R
authors.initials: VR
authors.lastname: Rao
authors.forename: Qin
authors.initials: Q
authors.lastname: Wang
authors.forename: Weixin
authors.initials: W
authors.lastname: Xu
authors.forename: Rebecca
authors.initials: R
authors.lastname: Cowling
authors.forename: Cheryl L
authors.initials: CL
authors.lastname: Nickerson-Nutter
authors.forename: Jay
authors.initials: J
authors.lastname: Gibbons
authors.forename: Jerry
authors.initials: J
authors.lastname: Skotnicki
authors.forename: Lih-Ling
authors.initials: LL
authors.lastname: Lin
authors.forename: Jeremy
authors.initials: J
authors.lastname: Levin
mesh_terms: D051722:ADAM Proteins; D000072198:ADAM17 Protein; D000818:Animals; D001169:Arthritis, Experimental / Q000188:drug therapy / Q000473:pathology; D001172:Arthritis, Rheumatoid / Q000188:drug therapy; D001682:Biological Availability; D002460:Cell Line; D003094:Collagen; D006801:Humans; D066298:In Vitro Techniques; D008070:Lipopolysaccharides; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors*; D045726:Metalloproteases / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D051379:Mice; D008811:Mice, Inbred DBA; D023282:Nuclease Protection Assays; D011480:Protease Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D011917:Rats, Inbred Lew; D013449:Sulfonamides / Q000493:pharmacokinetics / Q000494:pharmacology*; D013583:Synovial Membrane / Q000187:drug effects; D013585:Synovitis / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: C499807:(2R, 3S)-2-(((4-(2-butynyloxy)phenyl)sulfonyl)amino)-N,3-dihydroxybutanamide; D008070:Lipopolysaccharides; D011480:Protease Inhibitors; D012333:RNA, Messenger; D013449:Sulfonamides; D014409:Tumor Necrosis Factor-alpha; D003094:Collagen; D045726:Metalloproteases; D051722:ADAM Proteins; D008666:Metalloendopeptidases; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human; C000606463:Adam17 protein, mouse; C000606464:Adam17 protein, rat