Spirocyclopentane as a Novel Scaffold for Potent Ghrelin Receptor Full Agonists

Muscle atrophy and cachexia are common comorbidities among patients suffering from cancer, chronic obstructive pulmonary disease, acquired immunodeficiency syndrome, and several other chronic diseases. The peptide hormone ghrelin exerts pleiotropic effects; it acts by stimulating growth hormone secretion and subsequent increase of insulin-like growth factor-1 levels, an important mediator of muscle growth and repair. Ghrelin also acts on inflammation, appetite, and adipogenesis and, therefore, has been considered a promising therapeutic target for catabolic conditions. We previously reported on the synthesis and properties of indane- and pyrrolidine-based series of ghrelin receptor full agonists, which led to a sustained increase of insulin-like growth factor-1 in a dog pharmacodynamic study. Herein, we report a subsequent lead optimization work that, taking advantage of the previous work on indanes and pyrrolidines, with the synthesis of only two dozen compounds, brought to the identification of compound 22 suitable for progression as a clinical candidate.