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Metabolism of (4‐Phenoxyphenylsulfonyl)methylthiirane, a Selective Gelatinase Inhibitor
Author(s) -
Celenza Giuseppe,
VillegasEstrada Adriel,
Lee Mijoon,
Boggess Bill,
Forbes Christopher,
Wolter William R.,
Suckow Mark A.,
Mobashery Shahriar,
Chang Mayland
Publication year - 2008
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/j.1747-0285.2008.00632.x
Subject(s) - chemistry , hydroxylation , thiirane , glutathione , metabolism , glucuronic acid , cysteine , in vivo , biochemistry , pharmacology , ring (chemistry) , enzyme , biology , organic chemistry , polysaccharide , microbiology and biotechnology
(4‐Phenoxyphenylsulfonyl)methylthiirane (compound 1 ) is a highly selective and potent inhibitor of gelatinases that shows considerable promise in animal models for cancer and stroke. The metabolism of compound 1 was investigated in mice, following intraperitoneal administration at 100 mg/kg. Eight metabolites were identified in plasma and urine. The primary routes of metabolism of 1 were hydroxylation at the para ‐position of the terminal phenyl ring, hydroxylation at the α‐methylene to the sulfonyl, which lead to the generation of a sulfinic acid, and cysteine conjugation of the thiirane ring. The cysteine adducts arose through addition of glutathione to the thiirane ring. The molecule is extensively metabolized and excreted in mice, yet it exhibits activity in vivo .