Water-Soluble MMP-9 Inhibitor Reduces Lesion Volume after Severe Traumatic Brain Injury
| Autor: | Mayland Chang, Jiancun Cui, María Raquel Juárez, Dusan Hesek, Elena Lastochkin, Zezong Gu, Valerie A. Schroeder, Brittany N. Tomlinson, Rasheeq Nizam, Zhenzhou Chen, William R. Wolter, Mark A. Suckow, Major Gooyit, Mijoon Lee, Shahriar Mobashery, Bill Boggess |
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| Rok vydání: | 2015 |
| Předmět: |
Male
Physiology Traumatic brain injury Cognitive Neuroscience Lesion volume Matrix Metalloproteinase Inhibitors Matrix metalloproteinase Pharmacology Biochemistry Article Cell Line Heterocyclic Compounds 1-Ring Inhibitory Concentration 50 Mice Animal model Pharmacokinetics medicine Animals Distribution (pharmacology) Sulfones Neurologic Examination Dose-Response Relationship Drug business.industry Water Cell Biology General Medicine Prodrug medicine.disease Mice Inbred C57BL Disease Models Animal Water soluble Matrix Metalloproteinase 9 Solubility Blood-Brain Barrier Area Under Curve Brain Injuries business Psychomotor Performance |
| Zdroj: | ACS Chemical Neuroscience. 6:1658-1664 |
| ISSN: | 1948-7193 |
| DOI: | 10.1021/acschemneuro.5b00140 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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