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

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

  • J Med Chem. 2018 Dec 27;61(24):11039-11060. doi: 10.1021/acs.jmedchem.8b00794.
Antoine Daina 1,  Claudio Giuliano 2,  Claudio Pietra 2,  Junbo Wang 3,  Yushi Chi 3,  Zack Zou 3,  Fugang Li 4,  Zhonghua Yan 4,  Yifan Zhou 4,  Angelo Guainazzi 5,  Silvina Garcia Rubio 5,  Vincent Zoete 1 6
Affiliations

Affiliations

  • 1 Molecular Modeling Group , SIB Swiss Institute of Bioinformatics , CH-1015 Lausanne , Switzerland.
  • 2 Research and Preclinical Development Department , Helsinn Healthcare , CH-6912 Lugano , Switzerland.
  • 3 Department of Medicinal Chemistry, Pharmacokinetics and Metabolism , Sundia MediTech , 388 Jialilue Road, Zhangjiang Hi-Tech Park , Shanghai 201203 , China.
  • 4 Department of Discovery Biology , HD Biosciences , 590 Ruiqing Road Zhangjiang East Campus , Shanghai 201201 , China.
  • 5 Research and Development Department , Helsinn Therapeutics (US), Inc. , Iselin , New Jersey 08830 , United-States.
  • 6 Department of Fundamental Oncology , Lausanne University, Ludwig Institute for Cancer Research , Route de la Corniche 9A , 1066 Epalinges , Switzerland.
PMID: 30265805 DOI: 10.1021/acs.jmedchem.8b00794
Abstract

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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