title: 1-Hydroxy-2-pyridinone-based MMP inhibitors: synthesis and biological evaluation for the treatment of ischemic stroke.
abstract: Matrix metalloproteinase-9 (MMP-9) has been implicated in the breakdown of the blood-brain barrier during cerebral ischemia. As a result, inhibition of MMP-9 may have utility as a therapeutic intervention in stroke. Towards this end, we have synthesized a series of 1-hydroxy-2-pyridinones that have excellent in vitro potency in inhibiting MMP-9 in addition to MMP-2. Representative compounds also demonstrate good efficacy in the mouse transient mid-cerebral artery occlusion (tMCAO) model of cerebral ischemia.
authors.affiliation: East Coast Research and Early Development, Johnson & Johnson Pharmaceutical Research and Development, Welsh & McKean Roads, Spring House, PA 19477, USA. yzhang5@prdus.jnj.com
authors.forename: Yue-Mei
authors.initials: YM
authors.lastname: Zhang
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Fan
authors.forename: Devraj
authors.initials: D
authors.lastname: Chakaravarty
authors.forename: Bangping
authors.initials: B
authors.lastname: Xiang
authors.forename: Robert H
authors.initials: RH
authors.lastname: Scannevin
authors.forename: Zhihong
authors.initials: Z
authors.lastname: Huang
authors.forename: Jianya
authors.initials: J
authors.lastname: Ma
authors.forename: Sharon L
authors.initials: SL
authors.lastname: Burke
authors.forename: Prabha
authors.initials: P
authors.lastname: Karnachi
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Rhodes
authors.forename: Paul F
authors.initials: PF
authors.lastname: Jackson
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D002545:Brain Ischemia / Q000188:drug therapy*; D004195:Disease Models, Animal; D020128:Inhibitory Concentration 50; D008297:Male; D061965:Matrix Metalloproteinase Inhibitors; D051379:Mice; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D011728:Pyridones / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D015032:Zinc / Q000737:chemistry / Q000378:metabolism
chemical_list: D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors; D011728:Pyridones; D013449:Sulfonamides; D015032:Zinc