Selective gelatinase inhibitor neuroprotective agents cross the blood-brain barrier.
SB-3CT, a potent and selective inhibitor of matrix metalloproteinase-2 and -9, has shown efficacy in several animal models of neurological diseases. One of the greatest challenges in the development of therapeutics for neurological diseases is the inability of drugs to cross the blood-brain barrier. A sensitive bioanalytical method based on ultraperformance liquid chromatography with multiple-reaction monitoring detection was developed to measure levels of SB-3CT, its active metabolite, the α-methyl analogue, and its p-hydroxy metabolite in plasma and brain. The compounds are rapidly absorbed and are readily distributed to the brain. The pharmacokinetic properties of these gelatinase inhibitors and the efficacy shown by SB-3CT in animal models of stroke, subarachnoid hemorrhage, and spinal cord injury indicate that this class of compounds holds considerable promise in the treatment of diseases of the central nervous system.
Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana 46556, USA.
Major
M
Gooyit
Mark A
MA
Suckow
Valerie A
VA
Schroeder
William R
WR
Wolter
Shahriar
S
Mobashery
Mayland
M
Chang
D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism*; D005260:Female; D006573:Heterocyclic Compounds, 1-Ring / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D008297:Male; D061965:Matrix Metalloproteinase Inhibitors / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018696:Neuroprotective Agents / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D013450:Sulfones / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology
D006573:Heterocyclic Compounds, 1-Ring; D061965:Matrix Metalloproteinase Inhibitors; D018696:Neuroprotective Agents; C429533:SB 3CT compound; D013450:Sulfones