Discovery of isoxazole voltage gated sodium channel blockers for treatment of chronic pain.
A series of novel isoxazole voltage gated sodium channel blockers have been synthesized and evaluated. Substitutions on the benzylic position of benzamide were investigated to determine their effect on Na(v)1.7 inhibitory potency. The spirocyclobutyl substitution had the most significant enhancement on Na(v)1.7 inhibitory activity.
Shao
Pengcheng P
PP
Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, NJ 07065, USA. pengcheng_shao@merck.com
Ye
Feng
F
Weber
Ann E
AE
Li
Xiaohua
X
Lyons
Kathryn A
KA
Parsons
William H
WH
Garcia
Maria L
ML
Priest
Birgit T
BT
Smith
McHardy M
MM
Felix
John P
JP
Williams
Brande S
BS
Kaczorowski
Gregory J
GJ
McGowan
Erin
E
Abbadie
Catherine
C
Martin
William J
WJ
McMasters
Daniel R
DR
Gao
Ying-Duo
YD
D000818:Animals; D002460:Cell Line; D002908:Chronic Disease; D006801:Humans; D007555:Isoxazoles / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D010146:Pain / Q000188:drug therapy* / Q000276:immunology; D051381:Rats; D026941:Sodium Channel Blockers / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D015222:Sodium Channels / Q000378:metabolism*; D013127:Spinal Nerves / Q000187:drug effects; D013329:Structure-Activity Relationship
D007555:Isoxazoles; D026941:Sodium Channel Blockers; D015222:Sodium Channels