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KMID : 0617320080190010067
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Journal of Pharmacetical Sceiences Ewha Womans University
2008 Volume.19 No. 1 p.67 ~ p.80
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Identification of human cytochrome P450 enzymes involved in the metabolism ofIN-1130, a novel activin receptor-like kinase-5 (ALK5) inhibitor
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Kim Y. W.
Kim Y. K.
Kim D.-K.
Sheen Y. Y.
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Abstract
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1.?The in vitro metabolism of 3-((5-(6-methylpyridin-2-yl)-4-(quinoxalin-6-yl)-1H-imidazol-2-yl)methyl)benzamide (IN-1130), a selective activin receptor-like kinase-5 (ALK5) inhibitor and a candidate drug for fibrotic disease, was studied.
2.?The cytochrome P450s (CYPs) responsible for metabolism of IN-1130 in liver microsomes of rat, mouse, dog, monkey and human, and in human CYP supersomes™, were identified using specific CYP inhibitors. The order of disappearance of IN-1130 in various liver microsomal systems studied was as follows: monkey, mouse, rat, human, and dog.
3.?Five distinct metabolites (M1?M5) were identified in all the above microsomes and their production was substantially inhibited by CYP inhibitors such as SKF-525A and ketoconazole. Among nine human CYP supersomes™ examined, CYP3A4, CYP2C8, CYP2D6*1, and CYP2C19 were involved in the metabolism of IN-1130, and the production of metabolites were significantly inhibited by specific CYP inhibitors. IN-1130 disappeared fastest in CYP2C8 supersomes. CYP3A4 produced four metabolites of IN-1130 (M1?M4), whereas supersomes expressing human FMO cDNAs, such as FMO1, FMO3, and FMO5, produced no metabolites.
4.?Hence, it is concluded that metabolism of IN-1130 is mediated by CYP3A4, CYP2C8, CYP2D6*1, and CYP2C19.
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KEYWORD
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IN-1130, activin receptor-like kinase-5 (ALK5) inhibitor, metabolism, cytochrome P450
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