Discovery and SAR of a novel series of GIRK1/2 and GIRK1/4 activators.
AUTHORS
Ramos-Hunter
SJSusan J ,
Engers
DW Darren W ,
Kaufmann
K Kristian ,
Du
Y Yu ,
Lindsley
CW Craig W ,
Weaver
CD C David ,
Sulikowski
GA Gary A .
Bioorganic & medicinal chemistry letters. 2013 9 15; 23(18).
5195-8
- PMID: 23916258[PubMed].
- PMCID: PMC4066871.
- NIHMSID: NIHMS589020
ABSTRACT
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.