Water-Soluble MMP-9 Inhibitor Reduces Lesion Volume after Severe Traumatic Brain Injury
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- 作者：Mijoon Lee ; Zhenzhou Chen ; Brittany N. Tomlinson ; Major Gooyit ; Dusan Hesek ; Mar铆a Raquel Ju谩rez ; Rasheeq Nizam ; Bill Boggess ; Elena Lastochkin ; Valerie A. Schroeder ; William R. Wolter ; Mark A. Suckow ; Jiancun Cui ; Shahriar Mobashery ; Zezong Gu ; Mayland Chang
- 刊名：ACS Chemical Neuroscience
- 出版年：2015
- 出版时间：October 21, 2015
- 年：2015
- 卷：6
- 期：10
- 页码：1658-1664
- 全文大小：319K
- ISSN：1948-7193
文摘
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.