1-Hydroxy-2-pyridinone-based MMP inhibitors: synthesis and biological evaluation for the treatment of ischemic stroke.
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.
Zhang
Yue-Mei
YM
East Coast Research and Early Development, Johnson & Johnson Pharmaceutical Research and Development, Welsh & McKean Roads, Spring House, PA 19477, USA. yzhang5@prdus.jnj.com
Fan
Xiaodong
X
Chakaravarty
Devraj
D
Xiang
Bangping
B
Scannevin
Robert H
RH
Huang
Zhihong
Z
Ma
Jianya
J
Burke
Sharon L
SL
Karnachi
Prabha
P
Rhodes
Kenneth J
KJ
Jackson
Paul F
PF
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
D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors; D011728:Pyridones; D013449:Sulfonamides; D015032:Zinc