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.