Details

Autor(en) / Beteiligte

• Swale, Daniel R
• Kurata, Haruto
• Kharade, Sujay V
• Sheehan, Jonathan
• Raphemot, Rene
• Voigtritter, Karl R
• Figueroa, Eric E
• Meiler, Jens
• Blobaum, Anna L
• Lindsley, Craig W
• Hopkins, Corey R
• Denton, Jerod S

Titel

ML418: The First Selective, Sub-Micromolar Pore Blocker of Kir7.1 Potassium Channels

Ist Teil von

• ACS chemical neuroscience, 2016-07, Vol.7 (7), p.1013-1023

Ort / Verlag

United States: American Chemical Society

Erscheinungsjahr

2016

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• The inward rectifier potassium (Kir) channel Kir7.1 (KCNJ13) has recently emerged as a key regulator of melanocortin signaling in the brain, electrolyte homeostasis in the eye, and uterine muscle contractility during pregnancy. The pharmacological tools available for exploring the physiology and therapeutic potential of Kir7.1 have been limited to relatively weak and nonselective small-molecule inhibitors. Here, we report the discovery in a fluorescence-based high-throughput screen of a novel Kir7.1 channel inhibitor, VU714. Site-directed mutagenesis of pore-lining amino acid residues identified glutamate 149 and alanine 150 as essential determinants of VU714 activity. Lead optimization with medicinal chemistry generated ML418, which exhibits sub-micromolar activity (IC50 = 310 nM) and superior selectivity over other Kir channels (at least 17-fold selective over Kir1.1, Kir2.1, Kir2.2, Kir2.3, Kir3.1/3.2, and Kir4.1) except for Kir6.2/SUR1 (equally potent). Evaluation in the EuroFins Lead Profiling panel of 64 GPCRs, ion-channels, and transporters for off-target activity of ML418 revealed a relatively clean ancillary pharmacology. While ML418 exhibited low CLHEP in human microsomes which could be modulated with lipophilicity adjustments, it showed high CLHEP in rat microsomes regardless of lipophilicity. A subsequent in vivo PK study of ML418 by intraperitoneal (IP) administration (30 mg/kg dosage) revealed a suitable PK profile (C max = 0.20 μM and T max = 3 h) and favorable CNS distribution (mouse brain/plasma K p of 10.9 to support in vivo studies. ML418, which represents the current state-of-the-art in Kir7.1 inhibitors, should be useful for exploring the physiology of Kir7.1 in vitro and in vivo.