title: The design, synthesis, and structure-activity relationships of a series of macrocyclic MMP inhibitors.
abstract: A series of succinate-derived hydroxamic acids incorporating a macrocyclic ring were designed, synthesized, and evaluated as inhibitors of matrix metalloproteinases. The inhibitors were designed based on the published X-ray crystal structure of batimastat (1) complexed with human neutrophil collagenase (MMP-8). The synthesized compounds were shown to inhibit selected MMPs in vitro with low nanomolar potency.
authors.affiliation: Pharmaceutical Products Division, Abbott Laboratories, Abbott Park, IL 60064, USA.
authors.forename: D H
authors.initials: DH
authors.lastname: Steinman
authors.forename: M L
authors.initials: ML
authors.lastname: Curtin
authors.forename: R B
authors.initials: RB
authors.lastname: Garland
authors.forename: S K
authors.initials: SK
authors.lastname: Davidsen
authors.forename: H R
authors.initials: HR
authors.lastname: Heyman
authors.forename: J H
authors.initials: JH
authors.lastname: Holms
authors.forename: D H
authors.initials: DH
authors.lastname: Albert
authors.forename: T J
authors.initials: TJ
authors.lastname: Magoc
authors.forename: I B
authors.initials: IB
authors.lastname: Nagy
authors.forename: P A
authors.initials: PA
authors.lastname: Marcotte
authors.forename: J
authors.initials: J
authors.lastname: Li
authors.forename: D W
authors.initials: DW
authors.lastname: Morgan
authors.forename: C
authors.initials: C
authors.lastname: Hutchins
authors.forename: J B
authors.initials: JB
authors.lastname: Summers
mesh_terms: D017364:Collagenases / Q000737:chemistry*; D018360:Crystallography, X-Ray; D015195:Drug Design; D006801:Humans; D006877:Hydroxamic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007202:Indicators and Reagents; D007700:Kinetics; D020784:Matrix Metalloproteinase 8; D061965:Matrix Metalloproteinase Inhibitors; D008958:Models, Molecular; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013386:Succinates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013876:Thiophenes / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D006877:Hydroxamic Acids; D007202:Indicators and Reagents; D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors; D013386:Succinates; D013876:Thiophenes; D010649:Phenylalanine; C080985:batimastat; D017364:Collagenases; D020784:Matrix Metalloproteinase 8