Synthesis and pharmacological evaluation of phenylethynyl[1,2,4]methyltriazines as analogues of 3-methyl-6-(phenylethynyl)pyridine

Carroll, F., Kotturi, S., Navarro, H., Mascarella, S., Gilmour, B., Smith, F. L., ... Dewey, W. L. (2007). Synthesis and pharmacological evaluation of phenylethynyl[1,2,4]methyltriazines as analogues of 3-methyl-6-(phenylethynyl)pyridine. Journal of Medicinal Chemistry, 50(14), 3388-3391. DOI: 10.1021/jm070078r

Procedures were developed for the synthesis of 3-methyl-5-phenylethynyl[1,2,4]triazine (4), 6-methyl-3-phenylethynyl[1,2,4]triazine (5), and 5-methyl-3-phenylethynyl[1,2,4]triazine (6a) as analogues of 2-methyl-6-(phenylethynyl)pyridine (2). The compounds were evaluated for antagonism of glutamate-mediated mobilization of internal calcium in an mGluR5 in vitro efficacy assay. The most potent of the three analogues was 6a. Twenty additional analogues of 6a were synthesized and evaluated for mGluR5 antagonist efficacy. The most potent compounds were 3-(3-methylphenylethynyl)-5-methyl[1,2,4]triazine (6b), 5-(3-chlorophenylethynyl)-5-methyl[1,2,4]triazine (6c), and 3-(3-bromophenylethynyl)-5-methyl[1,2,4]triazine (6d).