Structure–Activity Relationship Studies of the Cyclic Depsipeptide Natural Product YM‐254890, Targeting the Gq Protein

Abstract Extracellular signals perceived by G protein‐coupled receptors are transmitted via G proteins, and subsequent intracellular signaling cascades result in a plethora of physiological responses. The natural product cyclic depsipeptides YM‐254890 and FR900359 are the only known compounds that specifically inhibit signaling mediated by the G q subfamily. In this study we exploit a newly developed synthetic strategy for this compound class in the design, synthesis, and pharmacological evaluation of eight new analogues of YM‐254890. These structure–activity relationship studies led to the discovery of three new analogues, YM‐13, YM‐14, and YM‐18, which displayed potent and selective G q inhibitory activity. This provides pertinent information for the understanding of the G q inhibitory mechanism by this class of compounds and importantly provides a pathway for the development of labeled YM‐254890 analogues.