新一代内向整流钾通道Kir2.1抑制剂的表征：VU6080824的发现

IF 4 3区医学 Q2 CHEMISTRY, MEDICINAL

ACS Medicinal Chemistry Letters Pub Date : 2025-08-29 DOI:10.1021/acsmedchemlett.5c00297

Renn A. Duncan, Daniel H. Haymer, Roman M. Lazarenko, Liangping Li, Yvette Blackwell, Emily L. Days, Srinivasan Krishnan, Analisa Thompson Gray, Olivier Boutaud, Darren W. Engers, Craig W. Lindsley*, Jerod S. Denton* and Aaron M. Bender*,

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引用次数: 0

摘要

ML133是向内整流钾通道Kir2.1的选择性抑制剂，已被广泛用作探测Kir生物学的工具。尽管ML133是一种工具化合物，但它只有适度的靶效（手动膜片钳（MPC） Kir2.1 IC50 = 1.5 μM, pH 7.4），其体内药代动力学（PK）此前尚未表征。在本研究中，我们报道了基于ML133支架的下一代Kir2.1抑制剂系列，以及ML133的大鼠PK和选定的类似物。化合物5s （VU6080824）在铊通量和MPC功能测定中均优于ML133，具有优良的PK性能，适合作为啮齿类动物改良的Kir2.1工具化合物使用。

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Characterization of Next-Generation Inhibitors for the Inward-Rectifier Potassium Channel Kir2.1: Discovery of VU6080824

ML133 is a selective inhibitor of the inward-rectifier potassium channel K_ir2.1 and has found extensive use as a tool with which to probe K_ir biology. Despite its utility as a tool compound, ML133 has only modest on-target potency (manual patch clamp (MPC) K_ir2.1 IC₅₀ = 1.5 μM, pH 7.4), and its in vivo pharmacokinetics (PK) were previously uncharacterized. In the present study, we report a next-generation series of K_ir2.1 inhibitors based on the ML133 scaffold, along with the rat PK of ML133 and selected analogs. Compound 5s (VU6080824) was ultimately identified as having superior potency to ML133 in both the thallium flux and MPC functional assays and has excellent PK properties suitable for use as an improved K_ir2.1 tool compound in rodents.

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来源期刊

ACS Medicinal Chemistry Letters CHEMISTRY, MEDICINAL-

CiteScore

7.30

自引率

2.40%

发文量

328

审稿时长

1 months

期刊介绍： ACS Medicinal Chemistry Letters is interested in receiving manuscripts that discuss various aspects of medicinal chemistry. The journal will publish studies that pertain to a broad range of subject matter, including compound design and optimization, biological evaluation, drug delivery, imaging agents, and pharmacology of both small and large bioactive molecules. Specific areas include but are not limited to: Identification, synthesis, and optimization of lead biologically active molecules and drugs (small molecules and biologics) Biological characterization of new molecular entities in the context of drug discovery Computational, cheminformatics, and structural studies for the identification or SAR analysis of bioactive molecules, ligands and their targets, etc. Novel and improved methodologies, including radiation biochemistry, with broad application to medicinal chemistry Discovery technologies for biologically active molecules from both synthetic and natural (plant and other) sources Pharmacokinetic/pharmacodynamic studies that address mechanisms underlying drug disposition and response Pharmacogenetic and pharmacogenomic studies used to enhance drug design and the translation of medicinal chemistry into the clinic Mechanistic drug metabolism and regulation of metabolic enzyme gene expression Chemistry patents relevant to the medicinal chemistry field.