Design, synthesis and evaluation of phenethylaminoheterocycles as K(v)1.5 inhibitors

Phenethylaminoheterocycles have been prepared and assayed for inhibition of the Kv1.5 potassium ion channel as a potential approach to the treatment of atrial fibrillation. A diverse set of heterocycles were identified as potent Kv1.5 inhibitors and were advanced to pharmacodynamic evaluation based on selectivity and pharmacokinetic profile. Heterocycle optimization and template modification lead to the identification of compound 24 which demonstrated increased atrial effective refractory period in the rabbit pharmacodynamic model with mild effects on blood pressure and heart rate.