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

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

  • ACS Med Chem Lett. 2025 Aug 29;16(9):1762-1771. doi: 10.1021/acsmedchemlett.5c00297.
Renn A Duncan 1 2,  Daniel H Haymer 1 2,  Roman M Lazarenko 3,  Liangping Li 4,  Yvette Blackwell 3,  Emily L Days 4,  Srinivasan Krishnan 1 2,  Analisa Thompson Gray 1 2,  Olivier Boutaud 1 2,  Darren W Engers 1 2,  Craig W Lindsley 1 2 5 6,  Jerod S Denton 2 3 4,  Aaron M Bender 1 2
Affiliations

Affiliations

  • 1 Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, Tennessee 37232, United States.
  • 2 Department of Pharmacology, Vanderbilt University, Nashville, Tennessee 37232, United States.
  • 3 Department of Anesthesiology, Vanderbilt University Medical Center, Nashville, Tennessee 37232, United States.
  • 4 VVanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, Tennessee 37232, United States.
  • 5 Department of Chemistry, Vanderbilt University, Nashville, Tennessee 37240, United States.
  • 6 Department of Biochemistry, Vanderbilt University, Nashville, Tennessee 37205, United States.
PMID: 40959251 DOI: 10.1021/acsmedchemlett.5c00297
Abstract

ML133 is a selective inhibitor of the inward-rectifier Potassium Channel Kir2.1 and has found extensive use as a tool with which to probe Kir biology. Despite its utility as a tool compound, ML133 has only modest on-target potency (manual patch clamp (MPC) Kir2.1 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 Kir2.1 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 Kir2.1 tool compound in rodents.

Keywords

SAR; deuterium; inward-rectifier potassium channel; manual patch clamp; pharmacokinetics; thallium flux.

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