In vitromicrosomal metabolic studies on a selective mGluR5 antagonist MTEP: Characterization ofin vitrometabolites 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.

Metabotropic Glutamate Receptor Subtype 5 Antagonists MPEP and MTEP

“…The major oxidative metabolites of MTEP are a hydroxymethyl metabolite, two oxides, a thiazole-ring opened metabolite and CO 2 (212). Metabolism of MTEP (1 ìM) in dog, monkey and human hepatic microsomes was similar (approximately 65%) (77).…”

Structure−Activity Relationships Comparing N-(6-Methylpyridin-yl)-Substituted Aryl Amides to 2-Methyl-6-(substituted-arylethynyl)pyridines or 2-Methyl-4-(substituted-arylethynyl)thiazoles as Novel Metabotropic Glutamate Receptor Subtype 5 Antagonists

“…On the basis of previous SAR studies,24 and concerns regarding in vivo toxicities with the thiazole “a” ring (ref 30 and personal communications with Drs. S. Barak Caine and Roger Spealman), we elected to retain only the 2-methyl-6- pyridyl “a” ring in the amide series.…”

The [18F]2-fluoro-1,3-thiazolyl moiety—an easily-accessible structural motif for prospective molecular imaging radiotracers

“…Here pairing of a substituted 1,3-thiazolyl group with a substituted phenyl group in the diarylacetylene provides ligands with similar or higher potency than the pairing of other aryl groups 11. Such 1,3-thiazoles appear susceptible to metabolism by oxidative ring opening 12. However, one report suggests that fluorination of a 1,3-thiazolyl group might lead to better resistance to metabolism in vivo 13.…”