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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

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.

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.