Abstract
SB-3CT is a potent and selective inhibitor of matrix metalloproteinase (MMP)-2 and -9, which has shown efficacy in an animal model of severe traumatic brain injury (TBI). However, SB-3CT is poorly water-soluble and is metabolized primarily to p-hydroxy SB-3CT (2), a more potent inhibitor than SB-3CT. We synthesized the O-phosphate prodrug (3) of compound 2 to enhance its water solubility by more than 2000-fold. The prodrug 3 was a poor MMP inhibitor, but readily hydrolyzed to the active 2 in human blood. Pharmacokinetics and brain distribution studies in mice showed that 2 crossed the blood-brain barrier (BBB) and achieved therapeutic concentrations in the brain. The prodrug 3/compound 2 was evaluated in a mouse model of severe TBI and found to significantly decrease the brain lesion volume and improve neurological outcomes. MMP-9 inhibition by a water-soluble thiirane inhibitor is a promising therapy for treatment of TBI.
Original language | English (US) |
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Pages (from-to) | 1658-1664 |
Number of pages | 7 |
Journal | ACS Chemical Neuroscience |
Volume | 6 |
Issue number | 10 |
DOIs | |
State | Published - Oct 21 2015 |
Bibliographical note
Publisher Copyright:© 2015 American Chemical Society.
Keywords
- MMP-9
- brain distribution
- prodrug
- traumatic brain injury