title: In vitro metabolic studies on the selective metabotropic glutamate receptor sub-type 5 (mGluR5) antagonist 3-[(2-methyl-1,3-thiazol-4-yl) ethynyl]-pyridine (MTEP).
abstract: Metabotropic glutamate receptors (mGluR) are G-protein-coupled receptors that play a major role in modulatory pathways in the CNS and have been suggested to have pharmacological implications in pain, psychiatric disorders and other neurological states. 3-[(2-Methyl-1,3-thiazol-4-yl) ethynyl]-pyridine (MTEP) is a specific and selective antagonist for the mGluR sub-type 5. Previous studies using rat liver microsomes showed that the major oxidative metabolites of MTEP are a hydroxymethyl metabolite (M1), two oxides (M2 and M4), a thiazole-ring opened metabolite (M3) and CO(2) (M5). In the present study, we examined the metabolism of MTEP in liver microsomes and expressed rat and human CYP isoforms. In rat liver microsomes, metabolic stability studies accurately predicted the in vivo clearance for MTEP. Incubation of MTEP with expressed rat and human CYP isoforms showed that CYP1A and CYP2C isoforms are primarily responsible for the metabolism of this compound. The results suggest that species differences in MTEP metabolism is possible and could contribute to specie-differences in biological effects of the compound.
authors.affiliation: Medicinal Chemistry, DMPK, Merck Research Laboratories San Diego, 3535 General Atomics Court, MRLSD B2-2200, San Diego, CA 92121, USA. mitchell_green@merck.com
authors.forename: Mitchell D
authors.initials: MD
authors.lastname: Green
authors.forename: Xiaoqing
authors.initials: X
authors.lastname: Yang
authors.forename: Merryl
authors.initials: M
authors.lastname: Cramer
authors.forename: Christopher D
authors.initials: CD
authors.lastname: King
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D006801:Humans; D066298:In Vitro Techniques; D008253:Macaca mulatta; D008297:Male; D008657:Metabolic Clearance Rate; D008862:Microsomes, Liver / Q000378:metabolism*; D011725:Pyridines / Q000737:chemistry* / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D013045:Species Specificity; D013844:Thiazoles / Q000737:chemistry* / Q000493:pharmacokinetics*
chemical_list: C472365:3-((2-methyl-1,3-thiazol-4-yl)ethynyl)pyridine; C578935:GRM5 protein, human; C578937:Grm5 protein, rat; D011725:Pyridines; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; D013844:Thiazoles