title: Discovery of potent and selective GIRK1/2 modulators via 'molecular switches' within a series of 1-(3-cyclopropyl-1-phenyl-1H-pyrazol-5-yl)ureas.
abstract: This Letter describes the on-going SAR efforts based on ML297, a potent, efficacious and selective GIRK1/2 activator (∼ 10-fold vs GIRK1/4 and inactive on GIRK2/3) via an iterative parallel synthesis approach. The chemical optimization at the 3-position of pyrazole within ML297 indicated that various functionalized 3-cyclopropyl moieties modulated GIRK pharmacology between inhibitor/activator within a series of 1-(3-cyclopropyl-1-phenyl-1H-pyrazol-5-yl)ureas. Importantly, novel 'molecular switches' that modulated the mode of pharmacology from inhibitor to activator was discovered on both the 3-cyclopropyl and N-phenyl moiety of the pyrazole core, providing the first highly selective GIRK1/2 activator.
authors.affiliation: College of Science, Northwest A&F University, Yangling, Shaanxi 712100, China; Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
authors.forename: Wandong
authors.initials: W
authors.lastname: Wen
authors.affiliation: College of Science, Northwest A&F University, Yangling, Shaanxi 712100, China. Electronic address: wuwenjun@nwsuaf.edu.cn.
authors.forename: Wenjun
authors.initials: W
authors.lastname: Wu
authors.affiliation: Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt Institute of Chemical Biology, Vanderbilt University/Vanderbilt University Medical Center, Nashville, TN 37232, USA.
authors.forename: C David
authors.initials: CD
authors.lastname: Weaver
authors.affiliation: Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt Specialized Chemistry Center for Probe Development (MLPCN), Nashville, TN 37232, USA; Department of Chemistry, Vanderbilt University, Nashville, TN 37232, USA; Vanderbilt Institute of Chemical Biology, Vanderbilt University/Vanderbilt University Medical Center, Nashville, TN 37232, USA. Electronic address: craig.lindsley@vanderbilt.edu.
authors.forename: Craig W
authors.initials: CW
authors.lastname: Lindsley
mesh_terms: D000818:Animals; D004353:Drug Evaluation, Preclinical; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008861:Microsomes / Q000378:metabolism; D010671:Phenylurea Compounds / Q000737:chemistry; D011485:Protein Binding; D011720:Pyrazoles / Q000737:chemistry*; D051381:Rats; D013329:Structure-Activity Relationship; D014508:Urea / Q000737:chemistry* / Q000378:metabolism
chemical_list: C587714:CID 56642816; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; D010671:Phenylurea Compounds; D011720:Pyrazoles; C031280:pyrazole; D014508:Urea
keywords: Activators; GIRK; Inhibitors; K(ir)3.x; Thallium flux