TY - JOUR
T1 - Water-soluble MMP-9 inhibitor prodrug generates active metabolites that cross the blood-brain barrier
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.
KW - MMP-9 inhibitor
KW - N -acetyltransferase
KW - blood-brain barrier
UR - https://www.scopus.com/pages/publications/84883256038
UR - https://www.scopus.com/pages/publications/84883256038#tab=citedBy
U2 - 10.1021/cn400077d
DO - 10.1021/cn400077d
M3 - Article
C2 - 23687970
AN - SCOPUS:84883256038
VL - 4
SP - 1168
EP - 1173
JO - ACS Chemical Neuroscience
JF - ACS Chemical Neuroscience
IS - 8
ER -