VU0134992 hydrochloride 是首个亚型偏好的，具有口服活性和选择性的内向整流钾通道Kir4.1阻滞剂，IC50为 0.97 μM。在 -120 mV 时，VU0134992 hydrochloride对同分 Kir4.1 比 Kir4.1/5.1 共分通道 (IC50=9 μM) 高出 9 倍的选择性。

VU0134992 hydrochloride is the first subtype-preferring, orally active and selective blocker of Kir4.1 potassium channel pore(IC50 : 0.97 μM).

In whole-cell patch-clamp electrophysiology experiments, VU0134992 inhibits Kir4.1 with an IC50 value of 0.97 M and is 9-fold selective for homomeric Kir4.1 over Kir4.1/5.1 concatemeric channels (IC50 = 9 M) at -120 mV.?In thallium (Tl+) flux assays, 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.?This potency and selectivity profile is superior to Kir4.1 inhibitors amitriptyline, nortriptyline, and fluoxetine.?Medicinal chemistry identified components of VU0134992 that are critical for inhibiting Kir4.1.?Patch-clamp electrophysiology, molecular modeling, and site-directed mutagenesis identified pore-lining glutamate 158 and isoleucine 159 as critical residues for block of the channel.

VU0134992 displayed a large free unbound fraction (fu) in rat plasma (fu = 0.213).?Consistent with the known role of Kir4.1 in renal function, oral dosing of VU0134992 led to a dose-dependent diuresis, natriuresis, and kaliuresis in rats.?Thus, VU0134992 represents the first in vivo active tool compound for probing the therapeutic potential of Kir4.1 as a novel diuretic target for the treatment of hypertension.

VU0134992 hydrochloride (250-300 g Male Sprague-Dawley rats;50 and 100 mg/kg) Oral gavage

1052515-91-9

C20H32BrClN2O2

447.84

VU0134992 hydrochloride

DMSO:230 mg/mL (513.58 mM),Need ultrasonic
Powder: -20°C for 3 years
In solvent: -80°C for 2 years