title: Water-Soluble MMP-9 Inhibitor Reduces Lesion Volume after Severe Traumatic Brain Injury.
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.forename: Mijoon
authors.initials: M
authors.lastname: Lee
authors.affiliation: Department of Pathology and Anatomical Sciences and Center for Translational Neuroscience, University of Missouri School of Medicine , Columbia, Missouri 65212, United States.
authors.forename: Zhenzhou
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Department of Pathology and Anatomical Sciences and Center for Translational Neuroscience, University of Missouri School of Medicine , Columbia, Missouri 65212, United States.
authors.forename: Brittany N
authors.initials: BN
authors.lastname: Tomlinson
authors.forename: Major
authors.initials: M
authors.lastname: Gooyit
authors.forename: Dusan
authors.initials: D
authors.lastname: Hesek
authors.affiliation: Department of Pathology and Anatomical Sciences and Center for Translational Neuroscience, University of Missouri School of Medicine , Columbia, Missouri 65212, United States.
authors.forename: María Raquel
authors.initials: MR
authors.lastname: Juárez
authors.affiliation: Department of Pathology and Anatomical Sciences and Center for Translational Neuroscience, University of Missouri School of Medicine , Columbia, Missouri 65212, United States.
authors.forename: Rasheeq
authors.initials: R
authors.lastname: Nizam
authors.forename: Bill
authors.initials: B
authors.lastname: Boggess
authors.forename: Elena
authors.initials: E
authors.lastname: Lastochkin
authors.forename: Valerie A
authors.initials: VA
authors.lastname: Schroeder
authors.forename: William R
authors.initials: WR
authors.lastname: Wolter
authors.forename: Mark A
authors.initials: MA
authors.lastname: Suckow
authors.affiliation: Department of Pathology and Anatomical Sciences and Center for Translational Neuroscience, University of Missouri School of Medicine , Columbia, Missouri 65212, United States.
authors.forename: Jiancun
authors.initials: J
authors.lastname: Cui
authors.forename: Shahriar
authors.initials: S
authors.lastname: Mobashery
authors.affiliation: Department of Pathology and Anatomical Sciences and Center for Translational Neuroscience, University of Missouri School of Medicine , Columbia, Missouri 65212, United States.
authors.forename: Zezong
authors.initials: Z
authors.lastname: Gu
authors.forename: Mayland
authors.initials: M
authors.lastname: Chang
mesh_terms: D000818:Animals; D019540:Area Under Curve; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism; D001930:Brain Injuries / Q000188:drug therapy* / Q000473:pathology* / Q000503:physiopathology; D002460:Cell Line; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006573:Heterocyclic Compounds, 1-Ring / Q000494:pharmacology / Q000627:therapeutic use*; D020128:Inhibitory Concentration 50; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D051379:Mice; D008810:Mice, Inbred C57BL; D009460:Neurologic Examination; D011597:Psychomotor Performance / Q000187:drug effects; D012995:Solubility; D013450:Sulfones / Q000494:pharmacology / Q000627:therapeutic use*; D014867:Water / Q000378:metabolism
chemical_list: D006573:Heterocyclic Compounds, 1-Ring; D061965:Matrix Metalloproteinase Inhibitors; C429533:SB 3CT compound; D013450:Sulfones; D014867:Water; D020780:Matrix Metalloproteinase 9
keywords: MMP-9; brain distribution; prodrug; traumatic brain injury