PAP‐1, a Selective Small Molecule Kv1.3 Blocker

Abstract

The lymphocyte K+ channel Kv1.3 constitutes an attractive target for the selective suppression of effector memory T (TEM) cells in autoimmune diseases such as multiple sclerosis, type-1 diabetes and psoriasis. Unfortunately, all of the existing small molecule Kv1.3 blockers are not selective and many of them like correolide, PAC and our own compound Psora-4 inhibit the cardiac K+ channel Kv1.5. Using Psora-4 as a template we identified a new series of phenoxyalkoxypsoralens, which exhibit 2 to 50-fold selectivity for Kv1.3 over Kv1.5. The most potent and “drug-like” compound of this series, PAP-1, blocks Kv1.3 with a Hill coefficient of 2 and an EC50 of 2 nM by preferentially binding to the C-type inactivated state of the channel. PAP-1 is 23-fold selective over Kv1.5, 33 to 125-fold selective over other Kv1-family channels and 500 to 7500-fold selective over Kv2.1, Kv3.1, Kv3.2, Kv4.2, HERG, calcium-activated K+ channels, Na+, Ca2+ and Cl− channels. PAP-1 potently inhibits the proliferation of human TEM cells and suppresses delayed type hypersensitivity, a CD4+ T cell mediated reaction, in rats when administered intraperitoneally or orally. PAP-1 further effectively treats allergic contact dermatitis, a CD8+ T cell mediated reaction. PAP-1 and several of its derivatives therefore constitute excellent new tools to further explore Kv1.3 as a target for immunosuppression. Supported by NMSS