Synthesis and SAR of 1,2- trans-(1-hydroxy-3-phenylprop-1-yl)cyclopentane carboxamide derivatives, a new class of sodium channel blockers

• Published in: Bioorganic & medicinal chemistry letters 2006-03, Vol.16 (5), p.1358-1361
• Main Authors: Ok, Dong, Li, Chunshi, Abbadie, Catherine, Felix, John P., Fisher, Michael H., Garcia, Maria L., Kaczorowski, Gregory J., Lyons, Kathryn A., Martin, William J., Priest, Birgit T., Smith, McHardy M., Williams, Brande S., Wyvratt, Matthew J., Parsons, William H.
• Format: Article
• Language: English
• Subjects: Analgesics; Animals; Biological and medical sciences; Cyclopentanes - chemical synthesis; Cyclopentanes - chemistry; Cyclopentanes - pharmacokinetics; Cyclopentanes - pharmacology; Ether-A-Go-Go Potassium Channels - metabolism; Humans; Inhibitory Concentration 50; Medical sciences; Molecular Structure; Neuropharmacology; Pharmacology. Drug treatments; Rats; Sodium Channel Blockers - chemical synthesis; Sodium Channel Blockers - chemistry; Sodium Channel Blockers - pharmacokinetics; Sodium Channel Blockers - pharmacology; Sodium Channels - metabolism; Structure-Activity Relationship
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2005.11.051

Novel cyclopentane-based 3-phenyl-1-hydroxypropyl compounds were evaluated for inhibitory activity against the peripheral nerve and sodium channel Na V1.7 and off-target activity against the cardiac potassium channel hERG. Novel cyclopentane-based 3-phenyl-1-hydroxypropyl compounds were evaluated for inhibitory activity against the peripheral nerve sodium channel Na V1.7 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 V1.7. A benchmark compound from this series displayed efficacy in rat models of inflammatory and neuropathic pain.