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Towards a TREK-1/2 (TWIK-Related K+ Channel 1 and 2) Dual Activator Tool Compound: Multi-dimensional Optimization of BL-1249

Towards a TREK-1/2 (TWIK-Related K+ Channel 1 and 2) Dual Activator Tool Compound: Multi-dimensional Optimization of BL-1249

Yuzo Iwaki, Kentaro Yashiro, Masaya Kokubo, Takahiro Mori, Joshua M Wieting, Kevin M McGowan, Thomas M Bridges, Darren W Engers, Jerod S Denton, Haruto Kurata, Craig W Lindsley

Bioorg Med Chem Lett. 2019 Jul 1;29(13):1601-1604.

PMID: 31072652

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 K2P potassium channels TREK-1 (K2P2.1) and TREK-2 (K2P10.1). 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 K2P 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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP18200130	BL-1249		18200-13-0	Price

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