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.
|
Authors | Mijoon 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 |
Journal | ACS chemical neuroscience
(ACS Chem Neurosci)
Vol. 6
Issue 10
Pg. 1658-64
(Oct 21 2015)
ISSN: 1948-7193 [Electronic] United States |
PMID | 26241578
(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)
|