Discovery and SAR of a novel series of GIRK1/2 and GIRK1/4 activators

Vanderbilt Institute of Chemical Biology, Vanderbilt University, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
Bioorganic & medicinal chemistry letters (Impact Factor: 2.42). 07/2013; 23(18). DOI: 10.1016/j.bmcl.2013.07.002
Source: PubMed


This Letter describes a novel series of GIRK activators identified through an HTS campaign. The HTS lead was a potent and efficacious dual GIRK1/2 and GIRK1/4 activator. Further chemical optimization through both iterative parallel synthesis and fragment library efforts identified dual GIRK1/2 and GIRK1/4 activators as well as the first examples of selective GIRK1/4 activators. Importantly, these compounds were inactive on GIRK2 and other non-GIRK1 containing GIRK channels, and SAR proved shallow.

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