ABSTRACT
A series of lactam sulfonamides has been discovered and optimized as inhibitors of the Kv1.5 potassium ion channel for treatment of atrial fibrillation. In vitro structure-activity relationships from lead structure C to optimized structure 3y are described. Compound 3y was evaluated in a rabbit PD-model and was found to selectively prolong the atrial effective refractory period at submicromolar concentrations.
Subject(s)
Kv1.5 Potassium Channel/antagonists & inhibitors , Lactams/chemistry , Potassium Channel Blockers/chemistry , Pyrrolidinones/chemistry , Sulfonamides/chemistry , Animals , Dogs , Half-Life , Humans , Kv1.5 Potassium Channel/metabolism , Potassium Channel Blockers/chemical synthesis , Potassium Channel Blockers/pharmacokinetics , Pyrrolidinones/chemical synthesis , Pyrrolidinones/pharmacokinetics , Rabbits , Rats , Structure-Activity Relationship , Sulfonamides/chemical synthesis , Sulfonamides/pharmacokineticsABSTRACT
Diphenylphosphinic amides and diphenylphosphine oxides have been synthesized and tested as inhibitors of the Kv1.5 potassium ion channel as a possible treatment for atrial fibrillation. In vitro structure-activity relationships are discussed and several compounds with Kv1.5 IC(50) values of <0.5 µM were discovered. Selectivity over the ventricular IKs current was monitored and selective compounds were found. Results from a rabbit PD-model are included.
Subject(s)
Amides/chemical synthesis , Amides/pharmacology , Kv1.5 Potassium Channel/antagonists & inhibitors , Oxides/chemical synthesis , Oxides/pharmacology , Phosphines/chemical synthesis , Phosphines/pharmacology , Amides/chemistry , Animals , Biphenyl Compounds/chemistry , Humans , Inhibitory Concentration 50 , Molecular Structure , Oxides/chemistry , Phosphines/chemistry , Phosphinic Acids/chemistry , Protein Binding/drug effects , Rabbits , Structure-Activity RelationshipABSTRACT
An extremely efficient asymmetric synthesis of a pyrrolidine azasugar was completed in only four steps in water, without the use of protecting groups and in 60% overall yield from a simple, achiral bis-electrophile.
