VU0134992

VU0134992 is the first subtype-preferring, orally active and selective Kir4.1 potassium channel pore blocker, with an IC₅₀ of 0.97 µM. VU0134992 is 9-fold selective for homomeric Kir4.1 over Kir4.1/5.1 concatemeric channels (IC₅₀=9 µM) at -120 mV^[1]. IC50 & Target: IC50: 0.97 µM (Kir4.1)^[1] In Vitro: VU0134992 is greater than 30-fold selective for Kir4.1 over Kir1.1, Kir2.1, and Kir2.2, is weakly active toward Kir2.3, Kir6.2/SUR1, and Kir7.1, and is equally active toward Kir3.1/3.2, Kir3.1/3.4, and Kir4.2^[1]. The selectivity of VU0134992 for Kir4.1 versus nine other members of the Kir channel family was evaluated at concentrations ranging from 0.3 nM to 30 µM in 11-point CRC experiments, using established Tl+ flux assays. VU0134992 inhibits Kir3.1/Kir3.2 (92% inhibition at 30 µM, IC₅₀=2.5 µM), Kir3.1/Kir3.4 (92% inhibition at 30 µM, IC₅₀=3.1 µM), and Kir4.2 (100% inhibition at 30 µM, IC₅₀=8.1 µM) with approximately the same efficacy and potency that VU0134992 inhibits Kir4.1 (100% at 30 µM, IC₅₀=5.2 µM)^[1]. In Vivo: VU0134992 (50-100 mg/kg; oral gavage) statistically significantly increased urinary Na⁺ as well as K⁺ excretion^[1].