Bepridil

Bepridil (CERM 1978 (free base); Org 5730) is an orally active non-selective calcium channel antagonist with multi-ion channel blocking activity. Bepridil modulates Calmodulin, the 20S proteasome, T-type/L-type calcium channels, cardiac sodium channels, multiple potassium channels, γ-secretase, β-secretase, and mitoK_ATP/sarcK_ATP channels. Bepridil acts as a hydroxyl radical scavenger, regulates mitochondrial and intracellular calcium handling, and exerts antiarrhythmic, antianginal, and cardioprotective effects. Bepridil alters amyloid precursor protein processing, reduces β-amyloid and thalamic calcium levels, restores seladin-1/DHCR24 expression, and improves sensorimotor recovery after cerebral ischemia. Bepridil also exhibits potent inhibitory effects on SARS-CoV-2 replication. Bepridil is used in studies related to stable angina, arrhythmias, cerebral ischemia, Alzheimer's disease, and SARS-CoV-2 infection^[1][2][3][4]. IC50 & Target:Calcium channel, Sodium channel, SARS-CoV-2^[1][2] In Vitro:Bepridil accumulates extensively in cat ileal smooth muscle, chick ventricular muscle, rabbit papillary muscle, and rat ventricular myocytes; it inhibits ATP-dependent calcium uptake in isolated rat and rabbit heart mitochondria; and it exhibits potent hydroxyl radical scavenging activity in cell-free in vitro assays^[1].
Bepridil exerts bidirectional regulation on sodium currents in neonatal rat cardiomyocytes: short-term exposure inhibits I_Na (IC₅₀ = 96.3 mM), while long-term exposure (EC₅₀ = 9.5 mM) upregulates Na⁺ currents by inhibiting 20S proteasome-mediated degradation of Nav1.5 protein^[2].

Bepridil directly inhibits purified 20S proteasome activity in a concentration-dependent manner in vitro; HEK‑Nav1.5 cell experiments confirm that its effect of upregulating Na⁺ current does not depend on the expression of cardiomyocyte-specific Ca²⁺ channels^[2].

Bepridil blocks Kir6.2+SUR2A sarcK_ATP channel currents in HEK-293 cells and opens mitoK_ATP channels in a concentration-dependent manner (EC₅₀ = 27.5 nM), leading to flavoprotein oxidation, attenuation of Ouabain (HY-B1457)-induced mitochondrial Ca²⁺ overload, and improvement of post-ischemic contractile function recovery in guinea pig cardiac preparations^[4].

Bepridil reduces myocardial contractility, heart rate, and oxygen consumption in isolated perfused rabbit hearts, and its coronary vasodilatory effect occurs only at low flow rates^[1].
Bepridil reduces the electrical activity of rabbit sinoatrial node cells by inhibiting the slow inward current, and at concentrations of 4-6 mmol/L, it decreases the automaticity of isolated rabbit sinoatrial node tissue, slows conduction, and prolongs the refractory period^[1].
Bepridil exerts differential repolarization effects on myocardial tissues of rabbits and dogs: it shortens the action potential duration of Purkinje fibers while prolonging that of ventricular muscle, and this effect is dose-dependent within the range of 0.1 to 10 mg/L; it also restores ATP content and cell viability in hypoxic rat ventricular myocytes^[1].
Bepridil accelerates the recovery of ischemia-induced end-diastolic contracture during reperfusion in isolated perfused rat hearts via coronary vasodilation, an effect independent of its negative inotropic activity^[1]. In Vivo:Bepridil (2.5 mg/kg/min; i.v.; continuous infusion) produces hemodynamic effects in pigs comparable to those in dogs, with no change in stroke volume^[1].
Bepridil (1.25-5 mg/kg; i.v.; single dose) exerts negative chronotropic and negative dromotropic effects in anesthetized and conscious dogs, reducing heart rate in intact or denervated canine hearts, increasing coronary blood flow and oxygenation levels; in conscious dogs with chronic heart block, it produces a biphasic chronotropic response that includes an initial reflex tachycardia, while in anesthetized dogs it induces direct negative chronotropic and transient vasodilatory hemodynamic effects, with sustained reductions in heart rate and myocardial oxygen consumption^[1].

Bepridil exhibits potent hydroxyl radical scavenging activity in alloxan-induced diabetic mice^[1].
Bepridil (50 mg/kg; p.o.; once daily; for 27 consecutive days) reduces soluble Aβ₄₂ by 57% and calcium levels by 71% in the ipsilateral thalamus of rats after transient middle cerebral artery occlusion, restores seladin-1 expression, and improves forelimb sensorimotor function in rats^[3].