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 journalArticlepeer-review

6 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 languageEnglish (US)
Pages (from-to)1168-1173
Number of pages6
JournalACS Chemical Neuroscience
Volume4
Issue number8
DOIs
StatePublished - Aug 21 2013

Keywords

  • MMP-9 inhibitor
  • N -acetyltransferase
  • blood-brain barrier

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