Towards a TREK-1/2 (TWIK-Related K+ Channel 1 and 2) dual activator tool compound: Multi-dimensional optimization of BL-1249.
Bioorg Med Chem Lett
; 29(13): 1601-1604, 2019 07 01.
Article
em En
| MEDLINE
| ID: mdl-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.
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MEDLINE
Assunto principal:
Tetra-Hidronaftalenos
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Tetrazóis
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Canais de Potássio de Domínios Poros em Tandem
Limite:
Humans
Idioma:
En
Ano de publicação:
2019
Tipo de documento:
Article