Synthesis and SAR of 1,2-trans-(1-hydroxy-3-phenylprop-1-yl)cyclopentane carboxamide derivatives, a new class of sodium channel blockers.
Novel cyclopentane-based 3-phenyl-1-hydroxypropyl compounds were evaluated for inhibitory activity against the peripheral nerve sodium channel Na(V)1.7 and off-target activity against the cardiac potassium channel hERG. The stereochemistry of the hydroxyl group and substitution on the phenyl rings with either fluorinated O-alkyl or alkyl groups were found to be critical for conferring potency against Na(V)1.7. A benchmark compound from this series displayed efficacy in rat models of inflammatory and neuropathic pain.
Ok
Dong
D
Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, NJ 07065, USA. dong_ok@merck.com
Li
Chunshi
C
Abbadie
Catherine
C
Felix
John P
JP
Fisher
Michael H
MH
Garcia
Maria L
ML
Kaczorowski
Gregory J
GJ
Lyons
Kathryn A
KA
Martin
William J
WJ
Priest
Birgit T
BT
Smith
McHardy M
MM
Williams
Brande S
BS
Wyvratt
Matthew J
MJ
Parsons
William H
WH
D000818:Animals; D003517:Cyclopentanes / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D051638:Ether-A-Go-Go Potassium Channels / Q000378:metabolism; D006801:Humans; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D051381:Rats; D026941:Sodium Channel Blockers / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D015222:Sodium Channels / Q000378:metabolism*; D013329:Structure-Activity Relationship
D003517:Cyclopentanes; D051638:Ether-A-Go-Go Potassium Channels; D026941:Sodium Channel Blockers; D015222:Sodium Channels