title: Synthesis and SAR of 1,2-trans-(1-hydroxy-3-phenylprop-1-yl)cyclopentane carboxamide derivatives, a new class of sodium channel blockers.
abstract: 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.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, NJ 07065, USA. dong_ok@merck.com
authors.forename: Dong
authors.initials: D
authors.lastname: Ok
authors.forename: Chunshi
authors.initials: C
authors.lastname: Li
authors.forename: Catherine
authors.initials: C
authors.lastname: Abbadie
authors.forename: John P
authors.initials: JP
authors.lastname: Felix
authors.forename: Michael H
authors.initials: MH
authors.lastname: Fisher
authors.forename: Maria L
authors.initials: ML
authors.lastname: Garcia
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Kaczorowski
authors.forename: Kathryn A
authors.initials: KA
authors.lastname: Lyons
authors.forename: William J
authors.initials: WJ
authors.lastname: Martin
authors.forename: Birgit T
authors.initials: BT
authors.lastname: Priest
authors.forename: McHardy M
authors.initials: MM
authors.lastname: Smith
authors.forename: Brande S
authors.initials: BS
authors.lastname: Williams
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Wyvratt
authors.forename: William H
authors.initials: WH
authors.lastname: Parsons
mesh_terms: 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
chemical_list: D003517:Cyclopentanes; D051638:Ether-A-Go-Go Potassium Channels; D026941:Sodium Channel Blockers; D015222:Sodium Channels