Work

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

Year: 2025

Type: article

Abstract: High Resolution Image Download MS PowerPoint Slide ML133 is a selective inhibitor of the inward-rectifier potassium channel K ir 2.1 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 ir 2.1 IC 50 = 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 ir 2.1 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 ir 2.1 tool compound in rodents.

Source: ACS Medicinal Chemistry Letters

DOI: 10.1021/acsmedchemlett.5c00297