Discovery of potent and use-dependent sodium channel blockers for treatment of chronic pain.
A new series of voltage-gated sodium channel blockers with potential for treatment of chronic pain is reported. Systematic structure-activity relationship studies, starting with compound 1, led to identification of potent analogs that displayed use-dependent block of sodium channels, were efficacious in pain models in vivo, and most importantly, were devoid of activity against the cardiac potassium channel hERG.
Liang
Jun
J
Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, NJ 07065, USA. jun_liang@merck.com
Brochu
Richard M
RM
Cohen
Charles J
CJ
Dick
Ivy E
IE
Felix
John P
JP
Fisher
Michael H
MH
Garcia
Maria L
ML
Kaczorowski
Gregory J
GJ
Lyons
Kathryn A
KA
Meinke
Peter T
PT
Priest
Birgit T
BT
Schmalhofer
William A
WA
Smith
McHardy M
MM
Tarpley
Jason W
JW
Williams
Brande S
BS
Martin
William J
WJ
Parsons
William H
WH
D002908:Chronic Disease; D006801:Humans; D008968:Molecular Conformation; D015335:Molecular Probes; D010146:Pain / Q000188:drug therapy*; D026941:Sodium Channel Blockers / Q000737:chemistry / Q000627:therapeutic use*
D015335:Molecular Probes; D026941:Sodium Channel Blockers