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

作者：Wen, Wandong; Wu, Wenjun^*; Weaver, C. David; Lindsley, Craig W.

来源：Bioorganic & Medicinal Chemistry Letters, 2014, 24(21): 5102-5106.

DOI：10.1016/j.bmcl.2014.08.061

• GIRK
• K(ir)3.x
• Activators
• Inhibitors
• Thallium flux

This Letter describes the on-going SAR efforts based on ML297, a potent, efficacious and selective GIRK1/2 activator (similar to 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.

• 出版日期2014-11-1
• 单位西北农林科技大学