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Identification of Human Cytochrome P450 Enzymes Involved in the Metabolism of IN-1130, a Novel Activin Receptor-Like kinase-5 (ALK5) Inhibitor

Identification of Human Cytochrome P450 Enzymes Involved in the Metabolism of IN-1130, a Novel Activin Receptor-Like kinase-5 (ALK5) Inhibitor

Y W Kim, Y K Kim, D-K Kim, Y Y Sheen

Xenobiotica. 2008 May;38(5):451-64.

PMID: 18421620

Abstract:

1. The in vitro metabolism of 3-((5-(6-methylpyridin-2-yl)-4-(quinoxalin-6-yl)-1H-imidazol-2-yl)methyl)benzamide (IN-1,130), 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-1,130 in liver microsomes of rat, mouse, dog, monkey and human, and in human CYP supersomestrade mark, were identified using specific CYP inhibitors. The order of disappearance of IN-1,130 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 supersomestrade mark examined, CYP3A4, CYP2C8, CYP2D6 1, and CYP2C19 were involved in the metabolism of IN-1,130, and the production of metabolites were significantly inhibited by specific CYP inhibitors. IN-1,130 disappeared fastest in CYP2C8 supersomes. CYP3A4 produced four metabolites of IN-1,130 (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-1,130 is mediated by CYP3A4, CYP2C8, CYP2D6 1, and CYP2C19.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP868612833	IN-1130		868612-83-3	Price

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