Why the study?
ML133 has only modest on-target potency for Kir2.1 and its in vivo pharmacokinetics were previously uncharacterized.
VU6080824 is a novel, potent Kir2.1 inhibitor with excellent pharmacokinetic properties suitable for use as a tool compound in rodent models.
Next-generation Kir2.1 inhibitors improve tool compounds; leaves open their role in cardiovascular research pending in vivo data.
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.
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Duncan et al. (2025) studied this question.
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