Characterization of Next-Generation Inhibitors for the Inward-Rectifier Potassium Channel K<sub>ir</sub>2.1: Discovery of VU6080824
ML133 is a selective inhibitor of the inward-rectifier potassium channel K<sub>ir</sub>2.1 and has found extensive use as a tool with which to probe K<sub>ir</sub> biology. Despite its utility as a tool compound, ML133 has only modest on-target potency (manual patch clamp (MPC) K<sub>ir</sub>2.1 IC<sub>50</sub> = 1.5 μM, pH 7.4), and its <i>in vivo</i> pharmacokinetics (PK) were previously uncharacterized. In the present study, we report a next-generation series of K<sub>ir</sub>2.1 inhibitors based on the ML133 scaffold, along with the rat PK of ML133 and selected analogs. Compound <b>5s</b> (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<sub>ir</sub>2.1 tool compound in rodents.
Authors
- Aaron M. Bender (ORCID: https://orcid.org/0000-0003-0432-1648)
- Daniel H. Haymer
- Darren W. Engers (ORCID: https://orcid.org/0000-0002-3633-3072)
- Emily Days
- Jerod S. Denton (ORCID: https://orcid.org/0000-0003-0032-8586)
- Krishnan Srinivasan
- Analisa Thompson Gray
- Craig W. Lindsley (ORCID: https://orcid.org/0000-0003-0168-1445)
- Roman M. Lazarenko (ORCID: https://orcid.org/0000-0003-0177-2961)
- Olivier G. Boutaud (ORCID: https://orcid.org/0000-0002-8910-0598)
- Liangping Li (ORCID: https://orcid.org/0000-0003-0691-4594)
- Renn A. Duncan
- Yvette Blackwell
Institutions
- Vanderbilt University (US)
- Institute of Chemical Biology and Fundamental Medicine (RU)
- Center for Discovery (US)
- Vanderbilt University Medical Center (US)
Publication Details
- Journal
- ACS Medicinal Chemistry Letters
- Published
- 2025-08-29
- DOI
- https://doi.org/10.1021/acsmedchemlett.5c00297
- Citations
- 2
- Primary Topic
- Ion channel regulation and function
- Type
- article
- Field-Weighted Citation Impact
- 1.61
Funders
- William K. Warren Foundation