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

Abstract

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.

Keywords :

• In vitro
• metabolites
• structure elucidation