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• First detailed SAR account around TREK1/2 activators. • First optimization campaign directed at BL-1249. • Discovery of new in vitro and in vivo tool compound, ONO-2960632/VU6011992. 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 2P potassium channels TREK-1 (K 2P 2.1) and TREK-2 (K 2P 10.1). 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 2P 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. [ABSTRACT FROM AUTHOR]