title: Discovery of CGS 27023A, a non-peptidic, potent, and orally active stromelysin inhibitor that blocks cartilage degradation in rabbits.
abstract: Structure-activity relationships of a lead hydroxamic acid inhibitor of recombinant human stromelysin were systematically defined by taking advantage of a concise synthesis that allowed diverse functionality to be explored at each position in a template. An ex vivo rat model and an in vivo rabbit model of stromelysin-induced cartilage degradation were used to further optimize these analogs for oral activity and duration of action. The culmination of these modifications resulted in CGS 27023A, a potent, orally active stromelysin inhibitor that blocks the erosion of cartilage matrix.
authors.affiliation: Research Department, Novartis Pharmaceuticals, Summit, New Jersey 07901, USA.
authors.forename: L J
authors.initials: LJ
authors.lastname: MacPherson
authors.forename: E K
authors.initials: EK
authors.lastname: Bayburt
authors.forename: M P
authors.initials: MP
authors.lastname: Capparelli
authors.forename: B J
authors.initials: BJ
authors.lastname: Carroll
authors.forename: R
authors.initials: R
authors.lastname: Goldstein
authors.forename: M R
authors.initials: MR
authors.lastname: Justice
authors.forename: L
authors.initials: L
authors.lastname: Zhu
authors.forename: S
authors.initials: S
authors.lastname: Hu
authors.forename: R A
authors.initials: RA
authors.lastname: Melton
authors.forename: L
authors.initials: L
authors.lastname: Fryer
authors.forename: R L
authors.initials: RL
authors.lastname: Goldberg
authors.forename: J R
authors.initials: JR
authors.lastname: Doughty
authors.forename: S
authors.initials: S
authors.lastname: Spirito
authors.forename: V
authors.initials: V
authors.lastname: Blancuzzi
authors.forename: D
authors.initials: D
authors.lastname: Wilson
authors.forename: E M
authors.initials: EM
authors.lastname: O'Byrne
authors.forename: V
authors.initials: V
authors.lastname: Ganu
authors.forename: D T
authors.initials: DT
authors.lastname: Parker
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001665:Binding Sites; D002356:Cartilage / Q000187:drug effects / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D006877:Hydroxamic Acids; D066298:In Vitro Techniques; D007700:Kinetics; D061965:Matrix Metalloproteinase Inhibitors; D008956:Models, Chemical; D011480:Protease Inhibitors / Q000494:pharmacology*; D011719:Pyrazines; D011817:Rabbits; D051381:Rats; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors; D013329:Structure-Activity Relationship; D013373:Substance P / Q000378:metabolism; D013449:Sulfonamides
chemical_list: C097658:CGS 27023A; D006877:Hydroxamic Acids; D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors; D011719:Pyrazines; D011994:Recombinant Proteins; D013449:Sulfonamides; D013373:Substance P