In vivo multiple metabolic pathways for a novel G protein-coupled receptor 119 agonist DS-8500a in rats: involvement of the 1,2,4-oxadiazole ring-opening reductive reaction in livers under anaerobic conditions

Abstract

1. A 1,2,4-oxadiazole ring-containing compound DS-8500a was developed as a novel G protein-coupled receptor 119 agonist. In vivo metabolic fates of [¹⁴C]DS-8500a differently radiolabeled in the benzene ring or benzamide side carbon in rats were investigated.

2. Differences in mass balances were observed, primarily because after the oxadiazole ring-opening and subsequent ring-cleavage small-molecule metabolites containing the benzene side were excreted in the urine, while those containing the benzamide side were excreted in the bile.

3. DS-8500a was detected at trace levels in urine and bile, demonstrating extensive metabolism prior to urinary/biliary excretion. At least 16 metabolite structures were proposed in plasma, urine, and bile samples from rats treated with [¹⁴C]DS-8500a.

4. Formation of a ring-opened metabolite (reduced DS-8500a) in hepatocytes of humans, monkeys, and rats was confirmed; however, it was not affected by typical inhibitors of cytochrome P450s, aldehyde oxidases, or carboxylesterases in human hepatocytes. Extensive formation of the ring-opened metabolite was observed in human liver microsomes fortified with an NADPH-generating system under anaerobic conditions.

5. These results suggest an in vivo unique reductive metabolism of DS-8500a is mediated by human non-cytochrome P450 enzymes.

Keywords:

• Metabolite identification
• 1,2,4-oxadiazole
• ring-opening and -cleaving reaction

Acknowledgements

The authors thank Daisuke Nakai for his careful reading of the document and scientific expertise. We also thank Sekisui Medical (Tokyo, Japan) for their expertly conducted experiments, Christine Knauf for technical assistance and Jonas Dinser for quantitative analysis of the metabolites by LC-MS.

Disclosure statement

CM, AW, TD, HS, TI, NW, and OA work for Daiichi Sankyo Co. Ltd, IS and VR work for Daiichi Sankyo Europe GmbH, the manufacturer of DS-8500a. The other authors declare that there are no conflicts of interest.