Use of Kv1.3 Blockers for Inflammatory Skin Conditions

Abstract

Recent results using animal models of inflammatory skin conditions have shown that blockers of the voltage-gated potassium channel, Kv1.3 hold great promise for clinical utility. Kv1.3 blockers act as immunosuppressants by modulating the various subsets of inflammatory T and B cells involved in autoimmune disorders. While peptidic inhibitors based on naturally occurring venoms demonstrate potent and selective Kv1.3 blockade, these require parenteral administration and may face potential immunogenicity problems. Small molecule blockers show considerable diversity, however selectivity over other Kv1- family channels has been difficult to achieve. More recent advances have added to the evidence that Kv1.3 channels are a suitable therapeutic target and that the development of novel and selective agents will herald new drugs for inflammatory skin disorders.

Structure–activity relationship exploration of Kv1.3 blockers based on diphenoxylate

“…Diphenoxylate has already been shown to be able to treat inflammatory skin conditions including the autoimmune disorder psoriasis 15, 16 and this clinical observation, though unproven in a large clinical trial, is consistent with modest Kv1.3 channel blockade 12 . Efforts to produce a suitable topical formulation of diphenoxylate would seem unlikely due to the side-effect potential of this narcotic agent.…”

“…Diphenoxylate also shows structural similarity to a number of Kv1.3 blockers (Figure 1) and when assessed it was found to block Kv1.3 channels with an IC 50 of 5 μM 12 . With a view to optimising the Kv1.3 blockade shown by diphenoxylate, we examined which elements of the chemical structure are required for biological activity.…”

“…In one study, the potent Kv1.3 blocking peptide ShK and a series of related analogues were able to treat both adoptive transfer and chronic relapsing experimental autoimmune encephalomyelitis (EAE) in rats 11 . Small molecule blockers of Kv1.3 channels have also been investigated 12 . The most potent of these compounds is PAP-1 (IC 50 2 nM) which has been shown to suppress delayed type hypersensitivity (DTH) and allergic contact dermatitis (ACD) in Lewis rats when dosed orally, by i.p.…”

Perturbation of intracellular K+ homeostasis with valinomycin promotes cell death by mitochondrial swelling and autophagic processes

“…Cl --free extracellular buffered saline solution with or without ionomycin the activity of K-channels [39]. Interestingly, blockade of K-channels not only suppresses inflammatory processes [40], but also apoptosis [1][2][3]. In the present study, we evaluated whether a decline in intracellular K ?…”

Spiro azepane-oxazolidinones as Kv1.3 potassium channel blockers: WO2010066840

“…Correolide for example affects all Kv1-family channels with equivalent affinity, and by blocking Kv1.1 channels increased the peristaltic activity of the gastrointestinal tract [63,64]. So far, the only small molecule Kv1.3 blockers that exhibit degrees of selectivity that seem acceptable for development are PAP-1, which exhibits 23-fold selectivity over the Kv1.5 and 33- to 125-fold selectivity over the rest of the Kv1-family channels [35], and several of the Bionomics compounds like the example shown in Figure 2, which has been reported to exhibit 37-fold selectivity over Kv1.5 [58,65]. While PAP-1 is currently in preclinical development for psoriasis, Bionomics seems to be developing their compounds for multiple sclerosis, rheumatoid arthritis and psoriasis.…”