Design of a Potent and Selective Small Molecule Kv1.5 Blocker

Abstract

The voltage-gated potassium channel Kv1.5 is being studied extensively as a potential target for treating atrial fibrillation and other life-threatening arrhythmias. Since Kv1.5 is expressed selectively in the human atrium and not in the ventricle, a potent and selective Kv1.5 blocker should therefore significantly increase the action potential duration (APD) of the atrium without affecting that of the ventricle. Unlike the existing anti-arrhythmic drugs such as amiodarone, sotalol etc. that block the Kv11.1 channel (hERG), a potent and selective Kv1.5 blocker should not induce dangerous and fatal proventricular arrhythmia.Phenoxyalkoxypsoralens (PAPs) are a class of compounds that has previously been described to block both the lymphocyte Kv1.3 and the cardiac Kv1.5 channel (Mol. Pharmacol. 2005). Through a combination of classical medicinal chemistry and traditional electrophysiology, we now studied the structure-activity relationship of PAPs with the aim of generating more selective Kv1.5 blockers. When the side chain phenyl ring of PAPs were decorated with a combination of electron-donating (methyl) and electron-withdrawing (nitro) groups as in PAP-22 {5-[3-(4-methyl-2-nitrophenoxy)-propoxy]psoralen}, the compounds exhibited a four to five fold increase in selectivity for Kv1.5 over Kv1.3. However, when we substituted the nitro group with a chloro group, as in PAP-25 {5-[2-chloro-4-methylphenoxy)propoxy]-psoralen}, more selective Kv1.3 blockers were generated. We are currently further investigating the effect of other strongly electron-withdrawing groups instead of the nitro group in order to increase the potency and selectivity of PAPs for Kv1.5 over Kv1.3. Other fused tricyclic rings containing 2-aminobenzothiazole are also being explored as a potential pharmacophore to design and develop Kv1.5 blockers.Supported by The Board of Regents Support Fund