The Role of Aldehyde Oxidase in the Metabolic Clearance of Substituted Benzothiazoles

Title:The Role of Aldehyde Oxidase in the Metabolic Clearance of Substituted Benzothiazoles

Volume: 14 Issue: 2

Author(s): Yohannes Teffera*, Jingzhou Liu, Paul Krolikowski and Zhiyang Zhao

Affiliation:

• Chimerix, 2505 Meridian Pkwy, Suite 100, Durham, NC 27713,United States

Keywords: Aldehyde oxidase, substituted Benzothiazole, in vitro metabolism, in vivo metabolism, clearance, metabolite identification.

Abstract:

Background: A group of substituted benzothiazoles from a research project was found to have low microsomal clearance. However, these compounds had very high clearance in vivo.

Methods: In the present study, the clearance mechanism of two of the structural analogs, was investigated in vitro and in vivo.

Results: In vitro studies showed the formation of corresponding non-P450 dependent oxidative metabolites in S9, cytosol, and hepatocytes. The in vitro formation of these metabolites was observed in mice, rats, non-human primates, and humans. The dog did not form the corresponding metabolites in any of the matrices. Inhibition studies with S9 fraction and incubation with human recombinant aldehyde oxidase (AO) showed that the formation of the corresponding metabolites was AO dependent. To investigate the role of this pathway in vivo, mice were dosed with compound A and bile and plasma were analyzed. Most of the metabolites in bile contained the AO-dependent oxidized benzothiazole moiety, indicating that metabolism involving AO was probably the main pathway for clearance. The same metabolites were also observed circulating in plasma. Mass spectrometric analysis of the metabolite showed that the oxidation was on the benzothiazole moiety, but the exact position could not be identified. Isolation of the metabolite of compound A and analysis by NMR confirmed the structure of the metabolite as C2 carbon oxidation of the thiazole ring resulting in carboxamide moiety. Further comparison of both metabolites with corresponding authentic standards confirmed the structures.

Conclusion: To our knowledge, such an observation of in vitro and in vivo oxidation of substituted benzothiazole by AO has not been reported before. The results helped the medicinal chemists design compounds that avoid AO-mediated metabolism and with better ADME property.

Cite this article as:

Teffera Yohannes *, Liu Jingzhou , Krolikowski Paul and Zhao Zhiyang , The Role of Aldehyde Oxidase in the Metabolic Clearance of Substituted Benzothiazoles, Drug Metabolism Letters 2021; 14 (2) . https://dx.doi.org/10.2174/1872312814666210405101419