Application of 1D and 2D 1H-NMR in the Structural Elucidation of a N-Glucuronidated Metabolite and Oxidized Metabolites Generated in Microsomal Incubation

Author(s): Julius L. Apuy, April Bai, David Paisner, Sayee G. Hegde, Mehran F. Moghaddam.

Journal Name: Drug Metabolism Letters

Volume 6 , Issue 4 , 2012

Become EABM
Become Reviewer


Metabolite identification can provide tremendous value in identifying metabolic soft-spots on molecules of interest and to evaluate the potential for generating reactive species. This information is useful in designing stable analogs with acceptable drug-like properties. Two key compounds were found to generate major metabolites that could not be elucidated by mass spectrometry. Nuclear Magnetic Resonance (NMR) is a non-destructive method to obtain structural information. It requires milligram quantities of putative metabolites, typically unavailable in early stage discovery projects. Herein, we demonstrated the application of NMR using microgram quantities of samples to identify the structures of the major metabolites of two discovery compounds. In the first case, we studied structural elucidation of a Nglucuronide on a pyrazole moiety using 1H-NMR due to the instability of the glucuronidated metabolite under mass spectrometric conditions. In the second example, we characterized two oxidized metabolites having identical mass fragmentation using 2D-NMR. In both cases, chemists incorporated these findings into designing analogs to improve metabolic stability.

Keywords: Mass Spectrometry, Phase I Metabolism, Phase II Metabolism, Nuclear Magnetic Resonance, Structural Elucidation, Early Drug Discovery.

Rights & PermissionsPrintExport Cite as

Article Details

Year: 2012
Page: [265 - 274]
Pages: 10
DOI: 10.2174/1872312811206040006
Price: $58

Article Metrics

PDF: 17