TY - JOUR
T1 - O -phenyl carbamate and phenyl urea thiiranes as selective matrix metalloproteinase-2 inhibitors that cross the blood-brain barrier
AU - Gooyit, Major
AU - Song, Wei
AU - Mahasenan, Kiran V.
AU - Lichtenwalter, Katerina
AU - Suckow, Mark A.
AU - Schroeder, Valerie A.
AU - Wolter, William R.
AU - Mobashery, Shahriar
AU - Chang, Mayland
PY - 2013/10/24
Y1 - 2013/10/24
N2 - Brain metastasis occurs in 20-40% of cancer patients. Treatment is mostly palliative, and the inability of most drugs to penetrate the brain presents one of the greatest challenges in the development of therapeutics for brain metastasis. Matrix metalloproteinase-2 (MMP-2) plays important roles in invasion and vascularization of the central nervous system and represents a potential target for treatment of brain metastasis. Carbonate, O-phenyl carbamate, urea, and N-phenyl carbamate derivatives of SB-3CT, a selective and potent gelatinase inhibitor, were synthesized and evaluated. The O-phenyl carbamate and urea variants were selective and potent inhibitors of MMP-2. Carbamate 5b was metabolized to the potent gelatinase inhibitor 2, which was present at therapeutic concentrations in the brain. In contrast, phenyl urea 6b crossed the blood-brain barrier, however, higher doses would result in therapeutic brain concentrations. Carbamate 5b and urea 6b show potential for intervention of MMP-2-dependent diseases such as brain metastasis.
AB - Brain metastasis occurs in 20-40% of cancer patients. Treatment is mostly palliative, and the inability of most drugs to penetrate the brain presents one of the greatest challenges in the development of therapeutics for brain metastasis. Matrix metalloproteinase-2 (MMP-2) plays important roles in invasion and vascularization of the central nervous system and represents a potential target for treatment of brain metastasis. Carbonate, O-phenyl carbamate, urea, and N-phenyl carbamate derivatives of SB-3CT, a selective and potent gelatinase inhibitor, were synthesized and evaluated. The O-phenyl carbamate and urea variants were selective and potent inhibitors of MMP-2. Carbamate 5b was metabolized to the potent gelatinase inhibitor 2, which was present at therapeutic concentrations in the brain. In contrast, phenyl urea 6b crossed the blood-brain barrier, however, higher doses would result in therapeutic brain concentrations. Carbamate 5b and urea 6b show potential for intervention of MMP-2-dependent diseases such as brain metastasis.
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U2 - 10.1021/jm401217d
DO - 10.1021/jm401217d
M3 - Article
C2 - 24028490
AN - SCOPUS:84886547274
SN - 0022-2623
VL - 56
SP - 8139
EP - 8150
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 20
ER -