5-hydroxyindole-2-carboxylic acid amides: novel histamine-3 receptor inverse agonists for the treatment of obesity

Pierson, Pascale David and Fettes, Alec and Freichel, Christian and Gatti-McArthur, Silvia and Hertel, Cornelia and Huwyler, Jörg and Mohr, Peter and Nakagawa, Toshito and Nettekoven, Matthias and Plancher, Jean-Marc and Raab, Susanne and Richter, Hans and Roche, Olivier and Rodríguez Sarmiento, Rosa María and Schmitt, Monique and Schuler, Franz and Takahashi, Tadakatsu and Taylor, Sven and Ullmer, Christoph and Wiegand, Ruby. (2009) 5-hydroxyindole-2-carboxylic acid amides: novel histamine-3 receptor inverse agonists for the treatment of obesity. Journal of Medicinal Chemistry, 52 (13). pp. 3855-3868.

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Official URL: http://edoc.unibas.ch/54616/

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Obesity is a major risk factor in the development of conditions such as hypertension, hyperglycemia, dyslipidemia, coronary artery disease, and cancer. Several pieces of evidence across different species, including primates, underscore the implication of the histamine 3 receptor (H(3)R) in the regulation of food intake and body weight and the potential therapeutic effect of H(3)R inverse agonists. A pharmacophore model, based on public information and validated by previous investigations, was used to design several potential scaffolds. Out of these scaffolds, the 5-hydroxyindole-2-carboxylic acid amide appeared to be of great potential as a novel series of H(3)R inverse agonist. Extensive structure-activity relationships revealed the interconnectivity of microsomal clearance and hERG (human ether-a-go-go-related gene) affinity with lipophilicity, artificial membrane permeation, and basicity. This effort led to the identification of compounds reversing the (R)-alpha-methylhistamine-induced water intake increase in Wistar rats and, further, reducing food intake in diet-induced obese Sprague-Dawley rats. Of these, the biochemical, pharmacokinetic, and pharmacodynamic characteristics of (4,4-difluoropiperidin-1-yl)[1-isopropyl-5-(1-isopropylpiperidin-4-yloxy)-1H-indol-2-yl]methanone 36 are detailed.
Faculties and Departments:05 Faculty of Science > Departement Pharmazeutische Wissenschaften > Pharmazie > Pharmaceutical Technology (Huwyler)
UniBasel Contributors:Huwyler, Jörg
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:American Chemical Society
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:29 Nov 2017 07:49
Deposited On:29 Nov 2017 07:49

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