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Paper | Regular issue | Vol 71, No. 9, 2007, pp.2011-2026
Published online, 15th June, 2007
DOI: 10.3987/COM-07-11096
Pilsicainide and Its Oxymethylene Analog: Facile Alternative Syntheses and in vitro Testing on Human Skeletal Muscle Sodium Channels

Claudio Bruno, Alessia Catalano, Jean-Francois Desaphy, Maria M. Cavalluzzi, Alessia Carocci, Antonella Dipalma, Carlo Franchini, Giovanni Lentini,* Diana Conte Camerino, and Vincenzo Tortorella

*Medicinal Chemistry Department, Faculty of Pharmacy, via E. Orabona 4, 70125 Bari, Italy

Abstract

Facile, alternative synthetic routes gave access to both pilsicainide [N-(2,6-dimethylphenyl)-2-tetrahydro-1H-pyrrolizin-7a(5H)-ylacetamide, 1], a well-known IC antiarrhythmic drug, and its oxymethylene analog 2. Both compounds were tested on human skeletal muscle voltage-gated sodium channels, hNav1.4, transfected in tsA201 cells. 7a-[2-(2,6-Dimethylphenoxy)ethyl]hexahydro-1H-pyrrolizine (2) behaved as a bioisostere of 1, exerting a 4-fold more potent use-dependent block.