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
  • 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.
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