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

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.
AuthorsMijoon 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
JournalACS chemical neuroscience (ACS Chem Neurosci) Vol. 6 Issue 10 Pg. 1658-64 (Oct 21 2015) ISSN: 1948-7193 [Electronic] United States
PMID26241578 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References
  • Heterocyclic Compounds, 1-Ring
  • Matrix Metalloproteinase Inhibitors
  • SB 3CT compound
  • Sulfones
  • Water
  • Matrix Metalloproteinase 9
Topics
  • Animals
  • Area Under Curve
  • Blood-Brain Barrier (drug effects, metabolism)
  • Brain Injuries (drug therapy, pathology, physiopathology)
  • Cell Line
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Heterocyclic Compounds, 1-Ring (pharmacology, therapeutic use)
  • Inhibitory Concentration 50
  • Male
  • Matrix Metalloproteinase 9 (metabolism)
  • Matrix Metalloproteinase Inhibitors (chemistry, pharmacology, therapeutic use)
  • Mice
  • Mice, Inbred C57BL
  • Neurologic Examination
  • Psychomotor Performance (drug effects)
  • Solubility
  • Sulfones (pharmacology, therapeutic use)
  • Water (metabolism)

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