Metabolism of 1-{3-[3-(4-cyanobenzyl)-3H-imidazol-4-yl]-propyl}-3-(6-methoxypyridin-3- yl)-1-(2-trifluoromethylb enzyl) thiourea (YH3945), a novel anti-cancer drug, in rats using the C-14-labeled compound

Abstract

The metabolism of a novel anti-cancer agent, 1-{3-[3-(4-cyanobenzyl)-3H-imidazol-4-yl]-propyl}-3-(6-methoxypyridin-3-yl)-1-(2-trifluoromethylbenzyl)thiourea (YH3945), was investigated in rats. Bile, plasma, feces, and urine were collected and analyzed by a high-performance liquid chromatography (HPLC) system equipped with ultraviolet (UV), mass spectrometric, and radioactivity detectors. After intravenous dosing, mean radiocarbon recovery was 74.4+/-1.3% with 62.4+/-1.2% in the feces and 12.0+/-0.5% in the urine. Biliary excretion of the radioactivity for the first 24 It period was approximately 32%, suggesting that YH3945 is cleared by hepatobiliary excretion. YH3945 was extensively metabolized to 21 different metabolites including glucuronide conjugates, and structures of the metabolites were elucidated based on MSn and NMR spectral analyses. The major metabolic pathways in the rat were identified as O-demethylation of methoxypyridine, N-debenzylation of imidazole, and hydroxylation. Cyclic metabolites were also identified; concomitant demethylation in the methoxypyridine moiety and hydroxylation at the C16 position might destroy the chemical stability of the compound and subsequently lead to non-enzymatic cyclization. Cyclic metabolites were characteristic of YH3945, and a non-enzymatic reaction mechanism for the formation of cyclic metabolites was postulated. Copyright (C) 2004 John Wiley Sons, Ltd.