Open AccessHistamine-3 Receptor Inverse Agonists for the Treatment of Obesity: Validation of the Target and Identification of Novel Series
Author(s) -
Pascale David Pierson,
Christian Freichel,
Silvia Gatti-Mac Arthur,
Cornelia Hertel,
Jörg Huwyler,
Peter J. Mohr,
Tatsuo Nakagawa,
Matthias Nettekoven,
JeanMarc Plancher,
Susanne Raab,
Hans G. Richter,
Olivier Roche,
Rosa Marı́a Rodrı́guez Sarmiento,
Monique Schmitt,
Franz Schuler,
Tadakatsu Takahashi,
Sven Taylor,
Christoph Ullmer,
Ruby Wiegand
Publication year - 2009
Publication title -
chimia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.387
H-Index - 55
eISSN - 2673-2424
pISSN - 0009-4293
DOI - 10.2533/chimia.2009.275
Subject(s) - inverse agonist , pharmacology , histamine , pharmacophore , herg , medicine , chemistry , dyslipidemia , obesity , receptor , endocrinology , biochemistry , agonist , potassium channel
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.