title: Pyran-containing sulfonamide hydroxamic acids: potent MMP inhibitors that spare MMP-1.
abstract: The SAR of a series of sterically hindered sulfonamide hydroxamic acids with relatively large P1' groups is described. The compounds typically spare MMP-1 while being potent inhibitors of MMP-13. The metabolically more stable compounds in the series contain either a monocyclic or bicyclic pyran ring adjacent to the hydroxamate group. Despite the sparing of MMP-1, pre-clinical and clinical studies revealed that fibrosis in rats and MSS in humans is still produced.
authors.affiliation: Pfizer Global Research & Development, Groton Laboratories, Eastern Point Road, Groton, CT 06340, USA. reiterla@groton.pfizer.com
authors.forename: Lawrence A
authors.initials: LA
authors.lastname: Reiter
authors.forename: Ralph P
authors.initials: RP
authors.lastname: Robinson
authors.forename: Kim F
authors.initials: KF
authors.lastname: McClure
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Jones
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Reese
authors.forename: Peter G
authors.initials: PG
authors.lastname: Mitchell
authors.forename: Ivan G
authors.initials: IG
authors.lastname: Otterness
authors.forename: Marcia L
authors.initials: ML
authors.lastname: Bliven
authors.forename: Jennifer
authors.initials: J
authors.lastname: Liras
authors.forename: Santo R
authors.initials: SR
authors.lastname: Cortina
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Donahue
authors.forename: James D
authors.initials: JD
authors.lastname: Eskra
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Griffiths
authors.forename: Mary E
authors.initials: ME
authors.lastname: Lame
authors.forename: Arturo
authors.initials: A
authors.lastname: Lopez-Anaya
authors.forename: Gary J
authors.initials: GJ
authors.lastname: Martinelli
authors.forename: Shunda M
authors.initials: SM
authors.lastname: McGahee
authors.forename: Sue A
authors.initials: SA
authors.lastname: Yocum
authors.forename: Lori L
authors.initials: LL
authors.lastname: Lopresti-Morrow
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Tobiassen
authors.forename: Marcie L
authors.initials: ML
authors.lastname: Vaughn-Bowser
mesh_terms: D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000737:chemistry; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism*; D053509:Matrix Metalloproteinase 13; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000378:metabolism; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D011714:Pyrans / Q000737:chemistry; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry
chemical_list: D006877:Hydroxamic Acids; D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors; D011714:Pyrans; D013449:Sulfonamides; C507079:MMP13 protein, human; D053509:Matrix Metalloproteinase 13; D020782:Matrix Metalloproteinases; D020781:Matrix Metalloproteinase 1