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 (10 nM-30 μM) inhibits both hK Ca 2.2 and hK Ca 2.3 channel currents in a concentration‐dependent fashion. AP14145 (10 μM) inhibits 50% of the hK Ca 1.1 current, 90% of the hK Ca 2.1 current and has no effect on hK Ca 3.1 channel. AP14145 (10 μM) increases the EC 50 of Ca 2+ on K Ca 2.3 channels from 0.36 to 1.2 μM[1]. AP14145 hydrochloride demonstrates an IC 50 in whole-cell patch clamp on the human SK3 channel of 1.3 μM. AP14145 inhibits hERG (K V 11.1) with an IC 50 of 71.8 μM and K ir 3.1/K ir 3.4 (I KACh ) with an IC 50 of 9.3 μM and does not produce any significant effects on K V 1.5 (I Kur ), K V 7.1/KCNE1 (I Ks ), K V 4.3/KChiP2 (I to ), and K ir 2.1 (I K1 ) in 30 μM or on Na V 1.5 (15 μM; I Na ) on a panel of cardiac ion channels. AP14145 (1-10 μM) produces no significant block of Ca V 1.2[2].

AP14145 (10 μM) increases the duration of the atrial effective refractory period (AERP) in isolated perfused rat hearts[1]. AP14145 (2.5 and 5 mg/kg; bolus injections (iv)) increases the duration of the atrial effective refractory period in male sprague-dawley rats (250-350 g, 1-3 months old)[1]. AP14145 (5 mg/kg; bolus injections) has a C max of 8355 nmol/L, a t ? of 24.3 minutes in landrace pigs (12-13 weeks old, 30-35 kg gilts)[2].