title: Structure-based design of TACE selective inhibitors: manipulations in the S1'-S3' pocket.
abstract: A series of beta-sulfonyl hydroxamate TACE inhibitors, bearing a butynylamino or a butynyloxy P1' group, was designed and synthesized. Of the compounds investigated, 22 has excellent potency against isolated TACE enzyme, shows good selectivity over MMP-2 and MMP-13, and oral activity in an in vivo mouse model of TNF-alpha production.
authors.affiliation: Chemical and Screening Sciences, Wyeth Research, 200 CambridgePark Drive, Cambridge, MA 02140, USA. ahuang@wyeth.com
authors.forename: Adrian
authors.initials: A
authors.lastname: Huang
authors.forename: Diane
authors.initials: D
authors.lastname: Joseph-McCarthy
authors.forename: Frank
authors.initials: F
authors.lastname: Lovering
authors.forename: Linhong
authors.initials: L
authors.lastname: Sun
authors.forename: Weiheng
authors.initials: W
authors.lastname: Wang
authors.forename: Weixin
authors.initials: W
authors.lastname: Xu
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhu
authors.forename: Junqing
authors.initials: J
authors.lastname: Cui
authors.forename: Yuhua
authors.initials: Y
authors.lastname: Zhang
authors.forename: Jeremy I
authors.initials: JI
authors.lastname: Levin
mesh_terms: D051722:ADAM Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000072198:ADAM17 Protein; D000818:Animals; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D006877:Hydroxamic Acids / Q000737:chemistry* / Q000494:pharmacology*; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000378:metabolism; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D006877:Hydroxamic Acids; D061965:Matrix Metalloproteinase Inhibitors; D014409:Tumor Necrosis Factor-alpha; D051722:ADAM Proteins; D020782:Matrix Metalloproteinases; D000072198:ADAM17 Protein; C000606463:Adam17 protein, mouse