title: Metabolic activation of indole-containing prostaglandin D2 receptor 1 antagonists: impacts of glutathione trapping and glucuronide conjugation on covalent binding.
abstract: 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.
authors.affiliation: Department of Medicinal Chemistry, Merck Frosst Canada Ltd, 16711 Transcanada Hwy., Kirkland, Qué., Canada H9H 3L1. jeanfrancois_levesque@merck.com
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Lévesque
authors.forename: Stephen H
authors.initials: SH
authors.lastname: Day
authors.forename: Nathalie
authors.initials: N
authors.lastname: Chauret
authors.forename: Carmai
authors.initials: C
authors.lastname: Seto
authors.forename: Laird
authors.initials: L
authors.lastname: Trimble
authors.forename: Kevin P
authors.initials: KP
authors.lastname: Bateman
authors.forename: José M
authors.initials: JM
authors.lastname: Silva
authors.forename: Carl
authors.initials: C
authors.lastname: Berthelette
authors.forename: Nicolas
authors.initials: N
authors.lastname: Lachance
authors.forename: Michael
authors.initials: M
authors.lastname: Boyd
authors.forename: Lianhai
authors.initials: L
authors.lastname: Li
authors.forename: Claudio F
authors.initials: CF
authors.lastname: Sturino
authors.forename: Zhaoyin
authors.initials: Z
authors.lastname: Wang
authors.forename: Robert
authors.initials: R
authors.lastname: Zamboni
authors.forename: Robert N
authors.initials: RN
authors.lastname: Young
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Nicoll-Griffith
mesh_terms: D000818:Animals; D004583:Electrons; D020719:Glucuronides / Q000096:biosynthesis; D005978:Glutathione / Q000378:metabolism*; D022781:Hepatocytes / Q000378:metabolism / Q000648:ultrastructure; D006801:Humans; D007211:Indoles / Q000819:agonists* / Q000737:chemistry / Q000378:metabolism*; D008862:Microsomes, Liver / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism; D051381:Rats; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors*; D011982:Receptors, Prostaglandin / Q000037:antagonists & inhibitors*
chemical_list: D020719:Glucuronides; D007211:Indoles; C518174:MK-0524; D011506:Proteins; D011971:Receptors, Immunologic; D011982:Receptors, Prostaglandin; D005978:Glutathione; C036293:prostaglandin D2 receptor