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.
Lévesque
Jean-François
JF
Department of Medicinal Chemistry, Merck Frosst Canada Ltd, 16711 Transcanada Hwy., Kirkland, Qué., Canada H9H 3L1. jeanfrancois_levesque@merck.com
Day
Stephen H
SH
Chauret
Nathalie
N
Seto
Carmai
C
Trimble
Laird
L
Bateman
Kevin P
KP
Silva
José M
JM
Berthelette
Carl
C
Lachance
Nicolas
N
Boyd
Michael
M
Li
Lianhai
L
Sturino
Claudio F
CF
Wang
Zhaoyin
Z
Zamboni
Robert
R
Young
Robert N
RN
Nicoll-Griffith
Deborah A
DA
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*
D020719:Glucuronides; D007211:Indoles; C518174:MK-0524; D011506:Proteins; D011971:Receptors, Immunologic; D011982:Receptors, Prostaglandin; D005978:Glutathione; C036293:prostaglandin D2 receptor