Synthesis and pharmacological evaluation of phenylethynyl[1,2,4]methyltriazines as analogues of 3-methyl-6-(phenylethynyl)pyridine.
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).
Carroll
F Ivy
FI
Center for Organic and Medicinal Chemistry, Research Triangle Institute, P.O. Box 12194, Research Triangle Park, North Carolina 27709, USA. fic@rti.org
Kotturi
Sharadsrikar V
SV
Navarro
Hernán A
HA
Mascarella
S Wayne
SW
Gilmour
Brian P
BP
Smith
Forrest L
FL
Gabra
Bichoy H
BH
Dewey
William L
WL
D004353:Drug Evaluation, Preclinical; D009682:Magnetic Resonance Spectroscopy; D011725:Pyridines / Q000737:chemistry*; D014227:Triazines / Q000138:chemical synthesis* / Q000494:pharmacology*
C522845:3-methyl-6-(phenylethynyl)pyridine; D011725:Pyridines; D014227:Triazines