Water-Soluble MMP-9 Inhibitor Reduces Lesion Volume after Severe Traumatic Brain Injury

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

doi:10.1021/acschemneuro.5b00140

Water-Soluble MMP-9 Inhibitor Reduces Lesion Volume after Severe Traumatic Brain Injury

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

Research output: Contribution to journal › Article › peer-review

21 Citations (SciVal)

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.

Original language	English
Pages (from-to)	1658-1664
Number of pages	7
Journal	ACS Chemical Neuroscience
Volume	6
Issue number	10
DOIs	https://doi.org/10.1021/acschemneuro.5b00140
State	Published - Oct 21 2015

Bibliographical note

Publisher Copyright:
© 2015 American Chemical Society.

Keywords

MMP-9
brain distribution
prodrug
traumatic brain injury

ASJC Scopus subject areas

Biochemistry
Physiology
Cognitive Neuroscience
Cell Biology

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10.1021/acschemneuro.5b00140

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Lee, M., Chen, Z., Tomlinson, B. N., Gooyit, M., Hesek, D., Juárez, M. R., Nizam, R., Boggess, B., Lastochkin, E., Schroeder, V. A., Wolter, W. R., Suckow, M. A., Cui, J., Mobashery, S., Gu, Z., & Chang, M. (2015). Water-Soluble MMP-9 Inhibitor Reduces Lesion Volume after Severe Traumatic Brain Injury. ACS Chemical Neuroscience, 6(10), 1658-1664. https://doi.org/10.1021/acschemneuro.5b00140

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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.",

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author = "Mijoon Lee and Zhenzhou Chen and Tomlinson, {Brittany N.} and Major Gooyit and Dusan Hesek and Ju{\'a}rez, {Mar{\'i}a Raquel} and Rasheeq Nizam and Bill Boggess and Elena Lastochkin and Schroeder, {Valerie A.} and Wolter, {William R.} and Suckow, {Mark A.} and Jiancun Cui and Shahriar Mobashery and Zezong Gu and Mayland Chang",

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Lee, M, Chen, Z, Tomlinson, BN, Gooyit, M, Hesek, D, Juárez, MR, Nizam, R, Boggess, B, Lastochkin, E, Schroeder, VA, Wolter, WR, Suckow, MA, Cui, J, Mobashery, S, Gu, Z & Chang, M 2015, 'Water-Soluble MMP-9 Inhibitor Reduces Lesion Volume after Severe Traumatic Brain Injury', ACS Chemical Neuroscience, vol. 6, no. 10, pp. 1658-1664. https://doi.org/10.1021/acschemneuro.5b00140

TY - JOUR

T1 - Water-Soluble MMP-9 Inhibitor Reduces Lesion Volume after Severe Traumatic Brain Injury

AU - Lee, Mijoon

AU - Chen, Zhenzhou

AU - Tomlinson, Brittany N.

AU - Gooyit, Major

AU - Hesek, Dusan

AU - Juárez, María Raquel

AU - Nizam, Rasheeq

AU - Boggess, Bill

AU - Lastochkin, Elena

AU - Schroeder, Valerie A.

AU - Wolter, William R.

AU - Suckow, Mark A.

AU - Cui, Jiancun

AU - Mobashery, Shahriar

AU - Gu, Zezong

AU - Chang, Mayland

PY - 2015/10/21

Y1 - 2015/10/21

N2 - 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.

AB - 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.

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Water-Soluble MMP-9 Inhibitor Reduces Lesion Volume after Severe Traumatic Brain Injury

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

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