title: Water-soluble mmp-9 inhibitor prodrug generates active metabolites that cross the blood-brain barrier.
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.
authors.forename: Wei
authors.initials: W
authors.lastname: Song
authors.forename: Zhihong
authors.initials: Z
authors.lastname: Peng
authors.forename: Major
authors.initials: M
authors.lastname: Gooyit
authors.forename: Mark A
authors.initials: MA
authors.lastname: Suckow
authors.forename: Valerie A
authors.initials: VA
authors.lastname: Schroeder
authors.forename: William R
authors.initials: WR
authors.lastname: Wolter
authors.forename: Mijoon
authors.initials: M
authors.lastname: Lee
authors.forename: Masajiro
authors.initials: M
authors.lastname: Ikejiri
authors.forename: Jiankun
authors.initials: J
authors.lastname: Cui
authors.forename: Zezong
authors.initials: Z
authors.lastname: Gu
authors.forename: Mayland
authors.initials: M
authors.lastname: Chang
mesh_terms: D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000032:analysis / Q000493:pharmacokinetics; D001812:Blood-Brain Barrier / Q000187:drug effects*; D001923:Brain Chemistry; D002853:Chromatography, Liquid; D005260:Female; D013058:Mass Spectrometry; D020780:Matrix Metalloproteinase 9 / Q000008:administration & dosage / Q000032:analysis / Q000493:pharmacokinetics*; D061965:Matrix Metalloproteinase Inhibitors / Q000008:administration & dosage / Q000032:analysis / Q000493:pharmacokinetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D013450:Sulfones / Q000032:analysis / Q000493:pharmacokinetics; D014018:Tissue Distribution
chemical_list: D061965:Matrix Metalloproteinase Inhibitors; C568509:ND 322; D013450:Sulfones; D001120:Arginine; D020780:Matrix Metalloproteinase 9