VU0134992 hydrochloride

本公司产品仅用于科研实验，不得用于人体或动物的临床与诊断

VU0134992 盐酸盐是第一个亚型偏好的、口服活性的、选择性的 Kir4.1 钾通道孔阻滞剂（IC50：0.97 μM）。

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 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.The selectivity of VU0134992 hydrochloride 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 hydrochloride 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).

VU0134992 hydrochloride (50-100 mg/kg; oral gavage) statistically significantly increased urinary Na+ as well as K+ excretion. Animal Model:Male Sprague-Dawley rats (250-300 g)Dosage:Oral gavage Administration:50 and 100 mg/kg Result:Statistically significantly increased urinary Na+ as well as K+ excretion.

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Cell Cycle/DNA Damage

Potassium Channel

Kir4.1

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1052515-91-9

447.84

C20H32BrClN2O2

>98% (HPLC)

DMSO:230 mg/mL (513.58 mM; Need ultrasonic)

Cl.CC(C)C1=CC=C(OCC(=O)NC2CC(C)(C)NC(C)(C)C2)C(Br)=C1

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(-20℃)

With Ice Pack

≥ 2 years