Benzamide derivatives as blockers of Kv1.3 ion channel

Use of Kv1.3 Blockers for Inflammatory Skin Conditions

“…A more potent derivative trans - N -propylcarbamoyloxy- PAC ( 9 ) (Figure 1), was subsequently synthesized showing improved activity (IC 50 50 nM) [65]. Once again only modest selectivity (2–6 fold) over other Kv1 channels was exhibited by these compounds.…”

“…Modifications to the 2-position of the 2-methoxy phenyl ring were tolerated while substituents in the 3 or 4 position reduced potency. The trans C1 carbamate compounds also showed better selectivity for Kv1.3 over the other Kv1 channels, although at present this appears to be insufficient for clinical utility [65]. …”

Potassium channel blockers as immunosuppressants

“…Binding of compound 2 appeared to occur to a C-type inactivated state of the channel. Subsequent measurements using inhibition of 86 Rb + efflux from CHO cells stably transfected with the Kv1.3 channel yielded an IC 50 value for Kv1.3 channel block of 50 nM for compound 2 [19]. This translated to an antiproliferative IC 50 value of 270 nM against anti-CD3 antibody-stimulated T cells.…”

“…Synthetically more tractable Kv1.3 benzamide-based blockers have been discovered by Merck, represented by compound 1 in Figure 1, in particular, the propyl analogue 2 [19][20][21]103]. Similarly to correolide and a number of other compounds with Kv1.3 blocking activity, this compound appears to bind to the inner (intracellular) face of the ion channel, in a water-filled hydrophobic cavity beneath the selectivity filter.…”

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

“…Solvay Pharmaceuticals, or now presumably Abbott, is thus joining the ranks of Pfizer and Merck, who have been pursuing Kv1.3 for immunosuppression since the early 1990s and identified dihydroquinoline, piperidine, nortriterpene- or benzamide type Kv1.3 blockers exemplified by CP-339818 [44–46], UK-78,282 [47,48], correolide [34,49,50,51] and trans- N -propyl-carbamoyloxy-PAC [52,53] (Figure 2). Other, later identified small molecule Kv1.3 blockers are the phenoxyalkoxypsoralens from the University of California exemplified by PAP-1 [35], a series of related khellin and khellinone derived compounds from a collaboration between the Walter and Eliza Hall Institute (WEHI) of Medical Research in Australia and Bionomics [54–58] and the leprosy drug clofazimine [38].…”