Novel cyclopentane dicarboxamide sodium channel blockers as a potential treatment for chronic pain.
A series of new voltage-gated sodium channel blockers were prepared based on the screening lead succinic diamide BPBTS. Replacement of the succinimide linker with the more rigid cyclic 1,2-trans-diamide linker was well tolerated. N-Methylation on the biphenylsulfonamide side of the amide moiety significantly reduced the clearance rate in rat pharmacokinetic studies.
Shao
Pengchang P
PP
Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, NJ 07065, USA.
Ok
Dong
D
Fisher
Michael H
MH
Garcia
Maria L
ML
Kaczorowski
Gregory J
GJ
Li
Chunshi
C
Lyons
Kathryn A
KA
Martin
William J
WJ
Meinke
Peter T
PT
Priest
Birgit T
BT
Smith
McHardy M
MM
Wyvratt
Matthew J
MJ
Ye
Feng
F
Parsons
William H
WH
D000284:Administration, Oral; D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D000700:Analgesics / Q000138:chemical synthesis / Q000494:pharmacology; D000818:Animals; D001713:Biphenyl Compounds / Q000737:chemistry; D003517:Cyclopentanes / Q000138:chemical synthesis / Q000494:pharmacology* / Q000627:therapeutic use; D015640:Ion Channel Gating / Q000187:drug effects; D008745:Methylation; D008801:Mexiletine / Q000494:pharmacology; D010146:Pain / Q000188:drug therapy*; D010147:Pain Measurement / Q000187:drug effects; D051381:Rats; D026941:Sodium Channel Blockers / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D013329:Structure-Activity Relationship; D013386:Succinates / Q000737:chemistry; D013449:Sulfonamides / Q000737:chemistry
D000577:Amides; D000700:Analgesics; D001713:Biphenyl Compounds; D003517:Cyclopentanes; D026941:Sodium Channel Blockers; D013386:Succinates; D013449:Sulfonamides; C502584:cyclopentane dicarboxamide; D008801:Mexiletine