Metabolic activation of indole-containing prostaglandin D2 receptor 1 antagonists: Impacts of glutathione trapping and glucuronide conjugation on covalent binding

Some DP1 receptor antagonists from an indole-containing series were shown to cause in vitro covalent binding to protein in rat and human liver microsomes. Glutathione trapping experiments along with in vitro labeling assays confirmed that the presence of a strong electron withdrawing group was necessary to abrogate in vitro covalent binding, leading to the discovery of MK-0524. Hepatocyte incubations and in vivo studies showed that acyl-glucuronide formation did not translate into covalent binding.

Graphical abstractImpacts of substituents on the indole-core of DP1 receptor antagonists on reactive metabolite formation and in vitro and in vivo covalent binding to liver proteins.Figure optionsDownload full-size imageDownload as PowerPoint slide