Referenced in: none

Automatically associated channels: Kir2.1 , Kir2.2 , Kir3.1 , Kir3.2

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.

Authors: Wandong Wen, Wenjun Wu, C David Weaver, Craig W Lindsley

Journal, date & volume: Bioorg. Med. Chem. Lett., 2014 Nov 1 , 24, 5102-6

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/25264075

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.