PubMed 23838260

Referenced in: none

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

Title: Discovery of 'molecular switches' within a GIRK activator scaffold that afford selective GIRK inhibitors.

Authors: Wandong Wen, Wenjun Wu, Ian M Romaine, Kristian Kaufmann, Yu Du, Gary A Sulikowski, C David Weaver, Craig W Lindsley

Journal, date & volume: Bioorg. Med. Chem. Lett., 2013 Aug 15 , 23, 4562-6

PubMed link:

This letter describes a multi-dimensional SAR campaign based on a potent, efficacious and selective GIRK1/2 activator (~10-fold versus GIRK1/4 and inactive on nonGIRK 1-containing GIRKs, GIRK 2 or GIRK2/3). Further chemical optimization through an iterative parallel synthesis effort identified multiple 'molecular switches' that modulated the mode of pharmacology from activator to inhibitor, as well as engendering varying selectivity profiles for GIRK1/2 and GIRK1/4. Importantly, these compounds were all inactive on nonGIRK1 containing GIRK channels. However, SAR was challenging as subtle structural modifications had large effects on both mode of pharmacology and GIRK1/2 and GIRK1/4 channel selectivity.