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Phenotypic and metabolic investigation of a CSF-1R kinase receptor inhibitor (BLZ945) and its pharmacologically active metabolite.

Krauser, Joel, Jin, Yi, Walles, Markus, Pfaar, Ulrike, Sutton, James, Wiesmann, Marion, Graf, Daniel, Pflimlin-Fritschy, Veronique, Wolf, Thierry, Camenisch, Gian P. and Swart, Pieter Jacob (2014) Phenotypic and metabolic investigation of a CSF-1R kinase receptor inhibitor (BLZ945) and its pharmacologically active metabolite. Xenbiotica. ISSN 0049-8254 (print), 1366-5928 (electronic)


1. 4-[2((1R,2R)-2-Hydroxycyclohexylamino)-benzothiazol-6-yloxyl]-pyridine-2-carboxylic acid methylamide (BLZ945) is a small molecule inhibitor of CSF-1R kinase activity within osteoclasts designed to prevent skeletal related events in metastatic disease. Key metabolites were enzymatically and structurally characterized to understand the metabolic fate of BLZ945 and pharmacological implications. The relative intrinsic clearances for metabolites were derived from in vitro studies using human hepatocytes, microsomes and phenotyped with recombinant P450 enzymes.

2. Formation of a pharmacologically active metabolite (M9) was observed in human hepatocytes. The M9 metabolite is a structural isomer (diastereomer) of BLZ945 and is about 4-fold less potent. This isomer was enzymatically formed via P450 oxidation of the BLZ945 hydroxyl group, followed by aldo–keto reduction to the alcohol (M9).

3. Two reaction phenotyping approaches based on fractional clearances were applied to BLZ945 using hepatocytes and liver microsomes. The fraction metabolized (fm) or contribution ratio was determined for each metabolic reaction type (oxidation, glucuronidation or isomerization) as well as for each metabolite. The results quantitatively illustrate contribution ratios of the involved enzymes and pathways, e.g. the isomerization to metabolite M9 accounted for 24% intrinsic clearance in human hepatocytes. In summary, contribution ratios for the Phase I and Phase II pathways can be determined in hepatocytes.

Item Type: Article
Additional Information: BLZ945 has already been disclosed, presented at various symposia and published in a peer reviewed journal by Novartis externally (See References). The metabolite structures of BLZ945 have not been disclosed externally.
Keywords: BLZ945, CSF-1R, M-CSF, macrophage colony stimulating factor, in vitro metabolism, biotransformation, metabolic isomerization, in vitro clearance, intrinsic clearance, CYP450 phenotyping, reaction phenotyping, cytochrome P450, P450, CYP450
Date Deposited: 13 Oct 2015 13:13
Last Modified: 13 Oct 2015 13:13


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