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J Med Chem. 2018 Oct 15. doi: 10.1021/acs.jmedchem.8b00794. [Epub ahead of print]

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

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Molecular Modeling Group , SIB Swiss Institute of Bioinformatics , CH-1015 Lausanne , Switzerland.
Research and Preclinical Development Department , Helsinn Healthcare , CH-6912 Lugano , Switzerland.
Department of Medicinal Chemistry, Pharmacokinetics and Metabolism , Sundia MediTech , 388 Jialilue Road, Zhangjiang Hi-Tech Park , Shanghai 201203 , China.
Department of Discovery Biology , HD Biosciences , 590 Ruiqing Road Zhangjiang East Campus , Shanghai 201201 , China.
Research and Development Department , Helsinn Therapeutics (US), Inc. , Iselin , New Jersey 08830 , United-States.
Department of Fundamental Oncology , Lausanne University, Ludwig Institute for Cancer Research , Route de la Corniche 9A , 1066 Epalinges , Switzerland.


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.

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