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

• Published in: Bioorganic & medicinal chemistry letters Vol. 23; no. 18; pp. 5195 - 5198
• Main Authors: Ramos-Hunter, Susan J., Engers, Darren W., Kaufmann, Kristian, Du, Yu, Lindsley, Craig W., Weaver, C. David, Sulikowski, Gary A.
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 15.09.2013; Elsevier
• Subjects: Activators; Animals; Chemistry; Chemistry, Medicinal; Chemistry, Organic; Dose-Response Relationship, Drug; Drug Discovery; G Protein-Coupled Inwardly-Rectifying Potassium Channels - metabolism; G-protein coupled receptors; GIRK; Kir3.x; Lead; Life Sciences & Biomedicine; Mice; Molecular Probes - chemical synthesis; Molecular Probes - chemistry; Molecular Probes - pharmacology; Molecular Structure; Pharmacology & Pharmacy; Physical Sciences; potassium channels; Science & Technology; Structure-Activity Relationship; structure-activity relationships; system optimization; Thallium flux; Activators; GIRK; Thallium flux; Kir3.x; MESSENGER-RNAS; K(ir)3.x; PROTEIN; CLONING; K+ CHANNELS; BRAIN
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2013.07.002

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.