289656-45-7

Senicapoc is an inhibitor of intermediate conductance calcium-activated potassium (IK_Ca1/K_Ca3.1) channels. It inhibits rubidium efflux from and dehydration of isolated human red blood cells (RBCs) induced by the calcium ionophore A23187 (Item No. 11016; IC₅₀s = 11 and 30 nM, respectively). Senicapoc (10 mg/kg twice per day) reduces IK_Ca1/K_Ca3.1 channel activity, increases potassium levels in RBCs, and decreases erythrocyte density in the SAD transgenic mouse model of sickle cell disease. It inhibits IL-2, IFN-γ, IL-12, and IL-17A production in CD3⁺ T cells stimulated with phorbol 12-myristate 13-acetate (PMA; Item No. 10008014) and ionomycin (Item Nos. 10004974 | 11932) when used at a concentration of 1 μM. Senicapoc (100 mg/kg) increases the paw withdrawal threshold in a rat model of chronic constriction injury (CCI) of the sciatic nerve.

Treatment of disorders mediated by a calcium activated intermediate conductance potassium ion channel antagonist.

Senicapoc (ICA-17043; bis(4-fluorophenyl)phenyl acetamide), a selective, highly potent Gardos channel blocker (IC50 = 11 nM), specifically inhibits the efflux of potassium from the RBCs of both SCD transgenic mice and human sickle cell disease patients. It is derived from clotrimazole-1, a KCNN4 inhibitor. Senicapoc is well tolerated by both healthy volunteers and patients with SCD and has favourable pharmacokinetics, with a long half-life permitting once-daily dosing. It was designed for long-term sickle cell disease therapy to avoid clotrimazole-1 side effects. Whereas Senicapoc is a potent inhibitor of WT KCNN4, its efficiency on mutated channels was unknown[1-2].

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[1] Raphael Rapetti-Mauss. “Senicapoc: a potent candidate for the treatment of a subset of hereditary xerocytosis caused by mutations in the Gardos channel.” Haematologica 101 11 (2016): e431–e435.
[2] Kenneth I Ataga. “Efficacy and safety of the Gardos channel blocker, senicapoc (ICA-17043), in patients with sickle cell anemia.” Blood (2008): 3991–7.