Synthesis and Pharmacological Evaluation of Phenylethynyl[1,2,4]methyltriazines as Analogues of 3-Methyl-6-(phenylethynyl)pyridine

Abstract

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).

Strain‐Promoted Reaction of 1,2,4‐Triazines with Bicyclononynes

“…29 We postulated that Negishi‐type cross‐coupling could be extended to include other N‐heterocycles, and therefore devised a synthetic strategy (Scheme ) that utilised iodotriazine 9 as the electrophilic coupling partner. Iodotriazine 9 was formed through diazotisation of aminotriazine with isopentyl nitrite in diiodomethane (Scheme ) 30. Fmoc‐iodoalanine methyl ester 11 was synthesised in three steps from serine methyl ester 10 28…”

mGluR5 antagonists that block calcium mobilization in vitro also reverse (S)-3,5-DHPG-induced hyperalgesia and morphine antinociceptive tolerance in vivo

“…We recently reported on the synthesis and in vitro effects of a series of phenylethyl[1,2,4]methyltriazines which are analogues of the classical mGluR5 anatgonist MPEP (Carroll et al, 2007). Some but not all of the compounds tested selectively antagonized glutamate-mediated mobilization of internal calcium in the mGluR5 assay without possessing any efficacy at the mGlu receptor subtype 1 (mGluR1).…”

“…The selective mGluR5 antagonist 2-methyl-6-(phenylethynyl)pyridine hydrochloride (MPEP) was purchased from Tocris Cookson Bioscience (Ellisville, MO, USA). Carroll et al, 2007). All test drugs as well as MPEP were dissolved in a mixture of 10% dimethyl sulfoxide, 20% cremophor, 70% distilled water.…”

Preparation of a series of 5-methyl-3-(substituted)-[1,2,4]triazines

“…5-Methyl-3-sulfonyl[1,2,4]triazine ( 11 ) was prepared as described previously. 6 The products 3a–f and 4a–f were isolated in moderate yields after chromatographic separation.…”

“…1–5 In a previous study, we discovered that 3-(substituted phenylethynyl)-5-methy[1,2,4]triazines ( 1 ) were potent antagonists of glutamate-mediated mobilization of internal calcium in an mGluR5 in vitro efficacy assay. 6 …”