AP14145 hydrochloride is a potent negative allosteric modulator of K Ca 2 (SK) channels, specifically targeting K Ca 2.2 (SK2) and K Ca 2.3 (SK3) channels with an IC 50 of 1.1 μM. Inhibition of AP14145 hydrochloride is highly influenced by S508 and A533 amino acids present in the channel. This compound effectively extends the atrial effective refractory period (AERP) in rats and exhibits antiarrhythmic properties in a Vernakalant-resistant porcine model of atrial fibrillation (AF).

KCa2.2:1.1 μM (IC50), KCa2.3:1.1 μM (IC50)

AP14145, at concentrations ranging from 10 nM to 30 μM, effectively inhibits the currents of hKCa2.2 and hKCa2.3 channels in a concentration-dependent manner. At a concentration of 10 μM, AP14145 inhibits 50% of the hKCa1.1 current and 90% of the hKCa2.1 current, while it does not affect hKCa3.1 channels. Additionally, at 10 μM, it increases the EC50 of Ca2+ on KCa2.3 channels from 0.36 to 1.2 μM. AP14145 hydrochloride exhibits an IC50 of 1.3 μM against the human SK3 channel in whole-cell patch clamp assays, inhibits hERG (KV11.1) with an IC50 of 71.8 μM, and Kir3.1/Kir3.4 (IKACh) with an IC50 of 9.3 μM. It has no significant effect on KV1.5 (IKur), KV7.1/KCNE1 (IKs), KV4.3/KChiP2 (Ito), and Kir2.1 (IK1) at 30 μM or on NaV1.5 (15 μM; INa) across a panel of cardiac ion channels. At concentrations between 1-10 μM, AP14145 does not significantly block CaV1.2 channels.

AP14145 at 10 μM extends the atrial effective refractory period (AERP) in isolated perfused rat hearts, demonstrating comparable effects with bolus intravenous injections of 2.5 and 5 mg/kg in male Sprague-Dawley rats (weighing 250-350 g and aged 1-3 months)[1]. Additionally, a dosage of 5 mg/kg in Landrace pigs (12-13 weeks old, weighing 30-35 kg) results in a maximum concentration (C max) of 8355 nmol/L and a half-life (t½) of 24.3 minutes[2].