Rational Design, Synthesis, and Pharmacological Characterization of Novel Ghrelin Receptor Inverse Agonists as Potential Treatment against Obesity-Related Metabolic Diseases

A new
chemotype of ghrelin inverse agonists was discovered through
chimeric design based on molecular scaffolds known as growth-hormone
secretagogue receptor (GHSR) modulators but with divergent pharmacodynamic
and pharmacokinetic properties. The structure–activities/properties
exploration led to compound 47, which displayed potent
human GHSR antagonism and inverse agonism in cellular assays (IC50 = 68 nM, EC50 = 29 nM), moderate oral bioavailability,
and notable brain penetration in rat (F = 27%, B/P ratio = 1.9). First in vivo studies
demonstrated effective reduction of food intake after oral or parenteral
administration to mouse (78% at 1 h and 38% at 8 h, respectively).
Further preclinical studies are needed to evaluate the most suited
mode of administration with the aim of promoting a first central-acting
ghrelin inverse agonist molecule to development, which would represent
a significant step toward therapeutic agents to treat metabolic disorders
related to obesity, such as type 2 diabetes mellitus.