Water-soluble MMP-9 inhibitor prodrug generates active metabolites that cross the blood-brain barrier

Wei Song; Zhihong Peng; Major Gooyit; Mark A. Suckow; Valerie A. Schroeder; William R. Wolter; Mijoon Lee; Masajiro Ikejiri; Jiankun Cui; Zezong Gu; Mayland Chang

doi:10.1021/cn400077d

Water-soluble MMP-9 inhibitor prodrug generates active metabolites that cross the blood-brain barrier

Wei Song, Zhihong Peng, Major Gooyit, Mark A. Suckow, Valerie A. Schroeder, William R. Wolter, Mijoon Lee, Masajiro Ikejiri, Jiankun Cui, Zezong Gu, Mayland Chang

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

10 Scopus citations

Abstract

MMP-9 plays a detrimental role in the pathology of several neurological diseases and, thus, represents an important target for intervention. The water-soluble prodrug ND-478 is hydrolyzed to the active MMP-9 inhibitor ND-322, which in turn is N-acetylated to the even more potent metabolite ND-364. We used a sensitive bioanalytical method based on ultraperformance liquid chromatography with multiple-reaction monitoring detection to measure levels of ND-478, ND-322, and ND-364 in plasma and brain after administration of ND-478 and the metabolites. ND-478 did not cross the blood-brain barrier, as was expected; however the active metabolites ND-322 and ND-364 distributed to the brain. The active compound after administration of either ND-478 or ND-322 is likely ND-364. ND-322 is N-acetylated in both brain and liver, but it is so metabolized preferentially in liver. Since N-acetyltransferases involved in the metabolism of ND-322 to ND-364 are polymorphic, direct administration of the N-acetylated ND-364 would achieve the requisite therapeutic levels in the brain.

Original language	English (US)
Pages (from-to)	1168-1173
Number of pages	6
Journal	ACS Chemical Neuroscience
Volume	4
Issue number	8
DOIs	https://doi.org/10.1021/cn400077d
State	Published - Aug 21 2013
Externally published	Yes

Keywords

MMP-9 inhibitor
N -acetyltransferase
blood-brain barrier

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abstract = "MMP-9 plays a detrimental role in the pathology of several neurological diseases and, thus, represents an important target for intervention. The water-soluble prodrug ND-478 is hydrolyzed to the active MMP-9 inhibitor ND-322, which in turn is N-acetylated to the even more potent metabolite ND-364. We used a sensitive bioanalytical method based on ultraperformance liquid chromatography with multiple-reaction monitoring detection to measure levels of ND-478, ND-322, and ND-364 in plasma and brain after administration of ND-478 and the metabolites. ND-478 did not cross the blood-brain barrier, as was expected; however the active metabolites ND-322 and ND-364 distributed to the brain. The active compound after administration of either ND-478 or ND-322 is likely ND-364. ND-322 is N-acetylated in both brain and liver, but it is so metabolized preferentially in liver. Since N-acetyltransferases involved in the metabolism of ND-322 to ND-364 are polymorphic, direct administration of the N-acetylated ND-364 would achieve the requisite therapeutic levels in the brain.",

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doi = "10.1021/cn400077d",

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AU - Song, Wei

AU - Peng, Zhihong

AU - Gooyit, Major

AU - Suckow, Mark A.

AU - Schroeder, Valerie A.

AU - Wolter, William R.

AU - Lee, Mijoon

AU - Ikejiri, Masajiro

AU - Cui, Jiankun

AU - Gu, Zezong

AU - Chang, Mayland

PY - 2013/8/21

Y1 - 2013/8/21

N2 - MMP-9 plays a detrimental role in the pathology of several neurological diseases and, thus, represents an important target for intervention. The water-soluble prodrug ND-478 is hydrolyzed to the active MMP-9 inhibitor ND-322, which in turn is N-acetylated to the even more potent metabolite ND-364. We used a sensitive bioanalytical method based on ultraperformance liquid chromatography with multiple-reaction monitoring detection to measure levels of ND-478, ND-322, and ND-364 in plasma and brain after administration of ND-478 and the metabolites. ND-478 did not cross the blood-brain barrier, as was expected; however the active metabolites ND-322 and ND-364 distributed to the brain. The active compound after administration of either ND-478 or ND-322 is likely ND-364. ND-322 is N-acetylated in both brain and liver, but it is so metabolized preferentially in liver. Since N-acetyltransferases involved in the metabolism of ND-322 to ND-364 are polymorphic, direct administration of the N-acetylated ND-364 would achieve the requisite therapeutic levels in the brain.

AB - MMP-9 plays a detrimental role in the pathology of several neurological diseases and, thus, represents an important target for intervention. The water-soluble prodrug ND-478 is hydrolyzed to the active MMP-9 inhibitor ND-322, which in turn is N-acetylated to the even more potent metabolite ND-364. We used a sensitive bioanalytical method based on ultraperformance liquid chromatography with multiple-reaction monitoring detection to measure levels of ND-478, ND-322, and ND-364 in plasma and brain after administration of ND-478 and the metabolites. ND-478 did not cross the blood-brain barrier, as was expected; however the active metabolites ND-322 and ND-364 distributed to the brain. The active compound after administration of either ND-478 or ND-322 is likely ND-364. ND-322 is N-acetylated in both brain and liver, but it is so metabolized preferentially in liver. Since N-acetyltransferases involved in the metabolism of ND-322 to ND-364 are polymorphic, direct administration of the N-acetylated ND-364 would achieve the requisite therapeutic levels in the brain.

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KW - N -acetyltransferase

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Water-soluble MMP-9 inhibitor prodrug generates active metabolites that cross the blood-brain barrier

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