5-HT2C Receptor Agonists for the Treatment of Obesity. Biological and Chemical Adventures
| العنوان: | 5-HT2C Receptor Agonists for the Treatment of Obesity. Biological and Chemical Adventures |
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| المؤلفون: | Jacques Mizrahi, M J Bickerdike, Ian Anthony Cliffe, Antony R. Knight, David R. Adams, Paul Hebeisen, Anne Bourson, Jean-Marc Plancher, Jon M. Bentley, Craig S. Malcolm, Agnès Bénardeau, Hans Richter, Steven P. Vickers, Caterina Bissantz, Guy A. Kennett, Sven Taylor, Stephan Röver |
| المصدر: | CHIMIA, Vol 58, Iss 9 (2004) |
| بيانات النشر: | Swiss Chemical Society, 2004. |
| سنة النشر: | 2004 |
| مصطلحات موضوعية: | Indole test, chemistry.chemical_classification, Chemistry, Stereochemistry, Monoamine oxidase, Sonogashira coupling, General Medicine, General Chemistry, 5-ht2c receptor agonist, Sulfamidate, Enzyme, Pyrroloindole, Moiety, Stereoselectivity, Obesity, Receptor, QD1-999, 5-HT receptor |
| الوصف: | Obesity is a major risk factor in the development of conditions such as hypertension, hyperglycemia, dyslipidemia, coronary artery disease and cancer. There is increasing evidence suggesting an important role for the 5-HT2C receptor in appetite control. Collaboration between F. Hoffmann-La Roche Ltd and Vernalis Research Ltd has allowed rapid construction of a solid structure–activity relationship around a pyrroloindole core. A one-pot Sonogashira reaction followed by nucleophilic double cyclisation allows an elegant and expedient route to this central motif. Introduction of a (2S)-aminopropyl group in place of the aminoethyl endogenous ligand side-chain enhanced the affinity at the 5-HT2C receptor and reduced affinity towards monoamine oxidase enzymes (MAO). Sulfamidate reagents were found to be very effective for the introduction of the 2-aminopropyl moiety in a stereoselective manner. The substitution at position 5 (indole numbering) was found to be crucial for both affinity and selectivity. Pyrroloindoles bearing an alkoxyether in this position exhibit promising pharmacokinetic parameters in rodent and significant reduction of food intake, after per os application. |
| تدمد: | 2673-2424 0009-4293 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::39cd2ca4e1c3625ee305ccf5a6fff84b https://doi.org/10.2533/000942904777677506 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....39cd2ca4e1c3625ee305ccf5a6fff84b |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 26732424 00094293 |
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