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Metabolism of 5-Isopropyl-6-(5-methyl-1,3,4-oxadiazol-2-yl)-N-(2-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (BMS-645737): Identification of an UnusualN-Acetylglucosamine Conjugate in the Cynomolgus Monkey
- Source :
- Drug Metabolism and Disposition. 36:2475-2483
- Publication Year :
- 2008
- Publisher :
- American Society for Pharmacology & Experimental Therapeutics (ASPET), 2008.
-
Abstract
- 5-Isopropyl-6-(5-methyl-1,3,4-oxadiazol-2-yl)-N-(2-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (BMS-645737) is a potent and selective vascular endothelial growth factor receptor-2 antagonist. In this study, liquid chromatography/tandem mass spectrometry and NMR were used to investigate the biotransformation of BMS-645737 in vitro and in the cynomolgus monkey, dog, mouse, and rat. Metabolic pathways for BMS-645737 included multistep processes involving both oxidation and conjugation reactions. For example, the 2-methyl-1H-pyrrolo moiety underwent cytochrome P450-catalyzed hydroxylation followed by oxidation to a carboxylic acid and then conjugation with taurine. Alternatively, the 5-methyl-1,3,4-oxadiazol-2-yl moiety was metabolized by hydroxylation and then conjugation with sulfate. The pyridin-5-yl group underwent direct glucuronidation in hepatocytes (dog, monkey, human) and conjugation with N-acetylglucosamine in the monkey. Conjugation with glutathione and processing along the mercapturic acid pathway was a minor metabolic pathway in vivo, although BMS-645737 did not form conjugates in the presence of glutathione-supplemented liver microsomes. Other minor biotransformation pathways included oxidative dehydrogenation, dihydroxylation, and hydrolytic opening of the oxadiazole ring followed by either deacetylation or hydrolysis of the resulting diacyl hydrazide. Whereas previous studies have shown the formation of N-acetylglucosamine conjugates of alcohols, arylamines, and other small molecules, this report describes the biotransformation of a heterocyclic aromatic amine via direct conjugation with N-acetylglucosamine.
- Subjects :
- Glycosylation
Magnetic Resonance Spectroscopy
Stereochemistry
Carboxylic acid
Glucuronidation
Pharmaceutical Science
Mice, Inbred Strains
Hydroxylation
Acetylglucosamine
Rats, Sprague-Dawley
Mice
chemistry.chemical_compound
Dogs
Cytochrome P-450 Enzyme System
Biotransformation
Tandem Mass Spectrometry
Animals
Bile
Humans
Moiety
Pyrroles
Mercapturic acid
Protein Kinase Inhibitors
Pharmacology
chemistry.chemical_classification
Molecular Structure
Triazines
Aromatic amine
Vascular Endothelial Growth Factor Receptor-2
Recombinant Proteins
Rats
Macaca fascicularis
chemistry
Dihydroxylation
Hepatocytes
Microsomes, Liver
Metabolic Networks and Pathways
Subjects
Details
- ISSN :
- 1521009X and 00909556
- Volume :
- 36
- Database :
- OpenAIRE
- Journal :
- Drug Metabolism and Disposition
- Accession number :
- edsair.doi.dedup.....17763d5d13428db66d51fa223de43d54