4-Phenoxybutoxy-substituted Heterocycles - a Structure-Activity Relationship Study of Blockers of the Lymphocyte Potassium Channel Kv1.3

摘要

The voltage-gated potassium channel Kv1.3 constitutes an attractive pharmacological target for the treatment of effector memory T cell-mediated autoimmune diseases such as multiple sclerosis and psoriasis. Using 5-methoxypsoralen (5-MOP, >1), a compound isolated from Ruta graveolens, as a template we previously synthesized 5-(4-phenoxybutoxy)psoralen (PAP-1, >2) which inhibits Kv1.3 with an IC50 of 2 nM. Since PAP-1 is more than 1000-fold more potent than 5-MOP, we here investigated whether attaching a 4-phenoxybutoxy side-chain to other heterocyclic systems would also produce potent Kv1.3 blockers. While 4-phenoxybutoxy substituted quinolines, quinazolines and phenanthrenes were inactive, 4-phenoxybutoxy substituted quinolinones, furoquinolines, coumarins or furochromones inhibited Kv1.3 with IC50s of 150 nM to 10 µM in whole-cell patch-clamp experiments. Our most potent new compound is 4-(4-phenoxybutoxy)-7H-furo[3,2-g]chromene-7-thione (>73, IC50 17 nM), in which the carbonyl oxygen of PAP-1 is replaced by sulfur. Taken together, our results demonstrate that the psoralen system is a crucial part of the pharmacophore of phenoxyalkoxypsoralen-type Kv1.3 blockers.