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Bioorg Med Chem Lett. 2007 Jun 1;17(11):3038-43. Epub 2007 Mar 23.

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

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  • 1Department of Medicinal Chemistry, Merck Frosst Canada Ltd, 16711 Transcanada Hwy., Kirkland, Qué., Canada H9H 3L1.


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.

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