Discovery and optimization of (R)-prolinol-derived agonists of the Growth Hormone Secretagogue receptor (GHSR)

The discovery and optimization of a novel series of prolinol-derived GHSR agonists is described. This series emerged from a 11,520-member solid-phase library targeting the GPCR protein superfamily, and the rapid optimization of low micromolar hits into single-digit nanomolar leads can be attributed to the solid-phase synthesis of matrix libraries, which revealed multiple non-additive structure–activity relationships. In addition, the separation of potent diastereomers highlighted the influence of the α-methyl stereochemistry of the phenoxyacetamide sidechain on GHSR activity.

Graphical abstractThe discovery of single-digit nanomolar full agonists (e.g., 10b) of the Growth Hormone Secretagogue receptor (GHSR) is reported, starting with a micromolar screening hit identified from a GPCR-targeted solid-phase library. The ‘library pedigree’ of this series greatly facilitated its rapid optimization.Figure optionsDownload full-size imageDownload as PowerPoint slide