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 unusual N-acetylglucosamine conjugate in the cynomolgus monkey.

Content Provider	Semantic Scholar
Author	Johnson, Benjamin M. Kamath, Amrita V. Leet, John E. Liu, Xiaohong Bhide, Rajeev S. Tejwani, Ravindra W. Zhang, Yueping Qian, Ligang Wei, D. Duan-Porter Lombardo, Louis John Shu, Yue-Zhong
Copyright Year	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.
File Format	PDF HTM / HTML
DOI	10.1124/dmd.108.022624
PubMed reference number	18787055
Journal	Medline
Volume Number	36
Issue Number	12
Alternate Webpage(s)	http://dmd.aspetjournals.org/content/dmd/36/12/2475.full.pdf
Alternate Webpage(s)	http://dmd.aspetjournals.org/content/dmd/early/2008/09/11/dmd.108.022624.full.pdf
Journal	Drug metabolism and disposition: the biological fate of chemicals
Language	English
Access Restriction	Open
Content Type	Text
Resource Type	Article