Histamine-3 Receptor Inverse Agonists for the Treatment of Obesity: Validation of the Target and Identification of Novel Series


  • Pascale David Pierson
  • Christoph Ullmer
  • Sven Taylor
  • Tadakatsu Takahashi
  • Franz Schuler
  • Monique Schmitt
  • Rosa María Rodríguez Sarmiento
  • Olivier Roche
  • Hans Richter
  • Susanne Raab
  • Jean-Marc Plancher
  • Matthias Nettekoven
  • Toshito Nakagawa
  • Peter Mohr
  • Jörg Huwyler
  • Cornelia Hertel
  • Silvia Gatti-Mac Arthur
  • Christian Freichel
  • Ruby Wiegand




Herg, Histamine-3 receptor, Inverse agonist, Obesity, Pharmacophore model


Obesity is a major risk factor for the development of conditions such as hypertension, hyperglycemia, dyslipidemia, coronary artery disease and cancer. Several pieces of evidence, including data in primates, have demonstrated the beneficial effects of histamine-3 receptor (H3R) inverse agonists in the regulation of food intake and body weight. A pharmacophore model based on selected published H3R ligands and validated by previous investigations, was used to identify the 5-oxy-2-carboxamide-indole core as a novel series of H3R inverse agonists. Extensive structure–activity relationship (SAR) investigations were rewarded by the identification of several compounds reversing (R)-?-methyl-histamine-induced water intake increase and reducing food intake/body weight in rodent models of obesity. Among those compounds, (4,4-difluoro-piperidin-1-yl)-[1-isopropyl-5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-methanone, selected as a lead compound, was exhibiting a promising profile, including excellent pharmacokinetic properties, good in vitro safety profile and high efficacy in a chronic rodent model of obesity.




How to Cite

P. D. Pierson, C. Ullmer, S. Taylor, T. Takahashi, F. Schuler, M. Schmitt, R. M. Rodríguez Sarmiento, O. Roche, H. Richter, S. Raab, J.-M. Plancher, M. Nettekoven, T. Nakagawa, P. Mohr, J. Huwyler, C. Hertel, S. Gatti-Mac Arthur, C. Freichel, R. Wiegand, Chimia 2009, 63, 275, DOI: 10.2533/chimia.2009.275.