2. Academic Validation
  3. Water-Soluble MMP-9 Inhibitor Reduces Lesion Volume after Severe Traumatic Brain Injury

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

  • ACS Chem Neurosci. 2015 Oct 21;6(10):1658-64. doi: 10.1021/acschemneuro.5b00140.
Mijoon Lee,  Zhenzhou Chen 1,  Brittany N Tomlinson 1,  Major Gooyit,  Dusan Hesek,  María Raquel Juárez 1,  Rasheeq Nizam 1,  Bill Boggess,  Elena Lastochkin,  Valerie A Schroeder,  William R Wolter,  Mark A Suckow,  Jiancun Cui 1,  Shahriar Mobashery,  Zezong Gu 1,  Mayland Chang
Affiliations

Affiliation

  • 1 Department of Pathology and Anatomical Sciences and Center for Translational Neuroscience, University of Missouri School of Medicine , Columbia, Missouri 65212, United States.
PMID: 26241578 DOI: 10.1021/acschemneuro.5b00140
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.

Keywords

MMP-9; brain distribution; prodrug; traumatic brain injury.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-12354
    99.59%, MMP2/9 抑制剂
    MMP
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