Synthesis, structure-activity relationship, and pharmacological profile of analogs of the ASIC-3 inhibitor A-317567.
The synthesis, structure-activity relationship (SAR), and pharmacological evaluation of analogs of the acid-sensing ion channel (ASIC) inhibitor A-317567 are reported. It was found that the compound with an acetylenic linkage was the most potent ASIC-3 channel blocker. This compound reversed mechanical hypersensitivity in the rat iodoacetate model of osteoarthritis pain, although sedation was noted. Sedation was also observed in ASIC-3 knockout mice, questioning whether sedation and antinociception are mediated via a non-ASIC-3 specific mechanism.
Department of Medicinal Chemistry, Merck Research Laboratories, Sumneytown Pike, P.O. Box 4, West Point, Pennsylvania 19486, USA. scott_d_kuduk@merck.com
Scott D
SD
Kuduk
Christina N
CN
Di Marco
Vera
V
Bodmer-Narkevitch
Sean P
SP
Cook
Matthew J
MJ
Cato
Aneta
A
Jovanovska
Mark O
MO
Urban
Michael
M
Leitl
Nova
N
Sain
Annie
A
Liang
Robert H
RH
Spencer
Stefanie A
SA
Kane
George D
GD
Hartman
Mark T
MT
Bilodeau
D062646:Acid Sensing Ion Channel Blockers / Q000138:chemical synthesis* / Q000494:pharmacology*; D062565:Acid Sensing Ion Channels / Q000096:biosynthesis / Q000187:drug effects*; D000700:Analgesics / Q000138:chemical synthesis* / Q000494:pharmacology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D055724:Electrophysiological Phenomena; D005620:Freund's Adjuvant; D007461:Iodoacetates; D007546:Isoquinolines / Q000138:chemical synthesis* / Q000494:pharmacology*; D008297:Male; D051379:Mice; D009281:Naphthalenes / Q000138:chemical synthesis* / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D010003:Osteoarthritis / Q000139:chemically induced / Q000188:drug therapy; D010146:Pain / Q000139:chemically induced / Q000188:drug therapy; D010147:Pain Measurement / Q000187:drug effects; D010812:Physical Stimulation; D004856:Postural Balance / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship
C506640:A-317567; C568267:ASIC1 protein, mouse; C508378:ASIC3 protein, mouse; D062646:Acid Sensing Ion Channel Blockers; D062565:Acid Sensing Ion Channels; D000700:Analgesics; D007461:Iodoacetates; D007546:Isoquinolines; D009281:Naphthalenes; D005620:Freund's Adjuvant