| Literature DB >> 23687970 |
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.
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.Entities:
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Year: 2013 PMID： 23687970 PMCID： PMC3750675 DOI： 10.1021/cn400077d
Source DB: PubMed Journal: ACS Chem Neurosci ISSN： 1948-7193 Impact factor: 4.418