Water-Soluble MMP-9 Inhibitor Reduces Lesion Volume after Severe Traumatic Brain Injury

Mijoon Lee, Zhenzhou Chen, Brittany N. Tomlinson, Major Gooyit, Dusan Hesek, María Raquel Juárez, Rasheeq Nizam, Bill Boggess, Elena Lastochkin, Valerie A. Schroeder, William R. Wolter, Mark A. Suckow, Jiancun Cui, Shahriar Mobashery, Zezong Gu, Mayland Chang

Research output: Contribution to journalArticle

13 Scopus citations

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 languageEnglish (US)
Pages (from-to)1658-1664
Number of pages7
JournalACS Chemical Neuroscience
Volume6
Issue number10
DOIs
StatePublished - Oct 21 2015

Keywords

  • MMP-9
  • brain distribution
  • prodrug
  • traumatic brain injury

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    Lee, M., Chen, Z., Tomlinson, B. N., Gooyit, M., Hesek, D., Juárez, M. R., Nizam, R., Boggess, B., Lastochkin, E., Schroeder, V. A., Wolter, W. R., Suckow, M. A., Cui, J., Mobashery, S., Gu, Z., & Chang, M. (2015). Water-Soluble MMP-9 Inhibitor Reduces Lesion Volume after Severe Traumatic Brain Injury. ACS Chemical Neuroscience, 6(10), 1658-1664. https://doi.org/10.1021/acschemneuro.5b00140