Subtype selective NMDA receptor antagonists: evaluation of some novel alkynyl analogues.
A benzylpiperidine analogue with an acetylenic linker, 5-(3-[4-(4-fluorobenzyl)-piperidin-1-yl]-prop-1-ynyl)-1,3-dihydrobenzimidazol-2-one (3), was identified as a chemical lead with excellent activity at the NR1A/2B receptor (IC50=3 nM). Efforts to optimize this activity led to focused modifications around the structural motif of 3. The synthesis and SAR studies are discussed.
Kornberg
Brian E
BE
Department of Chemistry, Pfizer Global Research and Development, 2800 Plymouth Road, Ann Arbor, MI 48105, USA. brian.kornberg@pfizer.com
Nikam
Sham S
SS
Wright
Jon L
JL
Kesten
Suzanne R
SR
Meltzer
Leonard T
LT
Coughenour
Linda
L
Barr
Bridget
B
Serpa
Kevin A
KA
McCormick
Julie
J
D000480:Alkynes / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D004353:Drug Evaluation, Preclinical / Q000379:methods; D018691:Excitatory Amino Acid Antagonists / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000378:metabolism
D000480:Alkynes; D018691:Excitatory Amino Acid Antagonists; D016194:Receptors, N-Methyl-D-Aspartate