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ID: ALA4665650
Journal: Bioorg Med Chem Lett
Title: Towards a TREK-1/2 (TWIK-Related K+ Channel 1 and 2) dual activator tool compound: Multi-dimensional optimization of BL-1249.
Authors: Iwaki Y,Yashiro K,Kokubo M,Mori T,Wieting JM,McGowan KM,Bridges TM,Engers DW,Denton JS,Kurata H,Lindsley CW
Abstract: This letter describes a focused, multi-dimensional optimization campaign around BL-1249, a fenamate class non-steroidal anti-inflammatory and a known activator of the K potassium channels TREK-1 (K2.1) and TREK-2 (K10.1). While BL-1249 has been widely profiled in vitro as a dual TREK-1/2 activator, poor physicochemical and DMPK properties have precluded a deeper understanding of the therapeutic potential of these key K channels across a broad spectrum of peripheral and central human disease. Here, we report multi-dimensional SAR that led to a novel TREK-1/2 dual activator chemotype, exemplified by ONO-2960632/VU6011992, with improved DMPK properties, representing a new lead for further optimization towards robust in vivo tool compounds.
CiteXplore: 31072652