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.
Department of Chemistry, Pfizer Global Research and Development, 2800 Plymouth Road, Ann Arbor, MI 48105, USA. brian.kornberg@pfizer.com
Brian E
BE
Kornberg
Sham S
SS
Nikam
Jon L
JL
Wright
Suzanne R
SR
Kesten
Leonard T
LT
Meltzer
Linda
L
Coughenour
Bridget
B
Barr
Kevin A
KA
Serpa
Julie
J
McCormick
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