In vitro microsomal metabolic studies on a selective mGluR5 antagonist MTEP: characterization of in vitro metabolites and identification of a novel thiazole ring opening aldehyde metabolite.
In vitro liver microsomal studies revealed that [14C] MTEP (3-[2-methyl-1,3-thiazol-4-yl)ethynyl] pyridine) was metabolized into three major oxidative metabolites. Metabolite 1 (M1) was shown to be a hydroxymethyl metabolite; M2 was shown to be a pyridine oxide. Moreover, a novel aldehyde metabolite (M3) was identified from mouse liver microsomes. The structure of the aldehyde M3 was elucidated by LC/MS/MS. In addition, methoxyamine, an aldehyde-trapping agent, and accurate mass measurement using a high-resolution quadrupole-time of flight (Q-TOF) instrument, were used to confirm the proposed thiazole ring-opening structure of M3. A mechanism for aldehyde M3 formation was postulated based on MTEP incubation studies with 18O2 and H2 18O using mouse liver microsomes. MTEP was initially oxidized at sulfur, followed by subsequent C4-C5 of thiazole epoxidation, thiozole ring opening and further oxidative desulfation. This proposed thiazole ring-opening mechanism might represent a novel metabolism pathway for xenobiotics containing a thiazole moiety. Species differences in the metabolism of MTEP were observed in mouse, rat, dog, monkey and human liver microsomes. Mouse appears to generate all three oxidative metabolites to a greater extent than other species examined.
Yang
X
X
Drug Metabolism and Pharmacokinetics Group, Department of Medicinal Chemistry, Merck Research Laboratories, San Diego, CA 92121, USA. jennifer_yang@sd.vrtx.com
Chen
W
W
D000447:Aldehydes / Q000378:metabolism; D000818:Animals; D006801:Humans; D008862:Microsomes, Liver / Q000378:metabolism*; D011725:Pyridines / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors*; D013844:Thiazoles / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology
C472365:3-((2-methyl-1,3-thiazol-4-yl)ethynyl)pyridine; D000447:Aldehydes; C578935:GRM5 protein, human; C578936:Grm5 protein, mouse; C578937:Grm5 protein, rat; D011725:Pyridines; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; D013844:Thiazoles