ABSTRACT
A series of isoindolinone compounds have been developed showing good in vitro potency on the Kv1.5 ion channel. By modification of two side chains on the isoindolinone scaffold, metabolically stable compounds with good in vivo PK profile could be obtained leaving the core structure unsubstituted. In this way, low microsomal intrinsic clearance (CLint) could be achieved despite a relatively high logD. The compounds were synthesized using the Ugi reaction, in some cases followed by Suzuki and Diels-Alder reactions, giving a diverse set of compounds in a small number of reaction steps.
Subject(s)
Isoindoles/pharmacology , Kv1.5 Potassium Channel/antagonists & inhibitors , Potassium Channel Blockers/pharmacology , Animals , Dose-Response Relationship, Drug , Humans , Isoindoles/chemical synthesis , Isoindoles/chemistry , Mice , Models, Animal , Molecular Structure , Potassium Channel Blockers/chemical synthesis , Potassium Channel Blockers/chemistry , Structure-Activity RelationshipABSTRACT
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.
