Identification and Optimization of Pyrrolidine Derivatives as Highly Potent Ghrelin Receptor Full Agonists

Muscle
atrophy and cachexia are common comorbidities among patients
suffering from cancer, chronic obstructive pulmonary disease, and
several other chronic diseases. The peptide hormone ghrelin exerts
pleiotropic effects including the stimulation of 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 an indane
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 on the identification of a series of pyrrolidine
or piperidine based full agonists and attempted optimization to give
compounds with profiles suitable for progression as clinical candidates.