JNJ0966 is a selective inhibitor of MMP-9 zymogen (IC50 = 440nM) that inhibits subsequent generation of the catalytically active enzyme. It showed no effect on the catalytic activity of MMP-1, MMP-2, MMP-3, MMP-9, or MMP-14, and did not inhibit the activation of MMP-2 zymogen.
Matrix metalloproteinases (MMP) are a family of proteolytic enzymes that participate in tissue remodeling and molecular signaling. MMP-9, a member of the MMP family, is excessively expressed in many human diseases. JNJ0966 is a selective inhibitor of MMP-9 zymogen (IC50 = 440nM) that inhibits subsequent generation of the catalytically active enzyme. It showed no effect on the catalytic activity of MMP-1, MMP-2, MMP-3, MMP-9, or MMP-14, and did not inhibit the activation of MMP-2 zymogen. The addition of JNJ0966 (10μM) resulted in a significant reduction in fully processed MMP-9. The administration of JNJ0966 at 10 and 30mg/kg via oral gavage reduced motor deficits in a mouse model of experimental autoimmune encephalomyelitis (EAE). JNJ0966 also partitioned into the brain of EAE mice with brain/plasma ratios of 6.2 for the 10mg/kg dose and 4.7 for the 30mg/kg dose[1].
作用机制
JNJ0966 interacts with a structural pocket in proximity to the MMP-9 zymogen cleavage site near Arg-106[1].
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