title: Synthesis and structure-activity relationship of a novel, achiral series of TNF-alpha converting enzyme inhibitors.
abstract: A novel series of achiral TNF-alpha converting enzyme (TACE) inhibitors has been discovered. These compounds exhibited activities from 0.35 to 11nM in a porcine TACE assay and inhibited TNF-alpha production in an LPS-stimulated whole blood assay with an IC(50) value of 23nM for the most potent one. They also have excellent selectivities over related metalloproteases including aggrecanases.
authors.affiliation: Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543-4000, USA. john.gilmore@bms.com
authors.forename: John L
authors.initials: JL
authors.lastname: Gilmore
authors.forename: Bryan W
authors.initials: BW
authors.lastname: King
authors.forename: Cathy
authors.initials: C
authors.lastname: Harris
authors.forename: Thomas
authors.initials: T
authors.lastname: Maduskuie
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Mercer
authors.forename: Rui-Qin
authors.initials: RQ
authors.lastname: Liu
authors.forename: Maryanne B
authors.initials: MB
authors.lastname: Covington
authors.forename: Mingxin
authors.initials: M
authors.lastname: Qian
authors.forename: Maria D
authors.initials: MD
authors.lastname: Ribadeneria
authors.forename: Krishna
authors.initials: K
authors.lastname: Vaddi
authors.forename: James M
authors.initials: JM
authors.lastname: Trzaskos
authors.forename: Robert C
authors.initials: RC
authors.lastname: Newton
authors.forename: Carl P
authors.initials: CP
authors.lastname: Decicco
authors.forename: James J-W
authors.initials: JJ
authors.lastname: Duan
mesh_terms: D051722:ADAM Proteins / Q000037:antagonists & inhibitors*; D000072198:ADAM17 Protein; D000818:Animals; D002460:Cell Line; D003500:Cyclization; D006801:Humans; D051379:Mice; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D011480:Protease Inhibitors; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human; C000606463:Adam17 protein, mouse