5-HT2C Receptor Agonists for the Treatment of Obesity. Biological and Chemical Adventures
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...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | deu |
| Published: |
Swiss Chemical Society
2004-09-01
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| Series: | CHIMIA |
| Subjects: | |
| Online Access: | https://chimia.ch/chimia/article/view/3877 |
| _version_ | 1811214272379748352 |
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| author | David Adams Sven Taylor Stephan Röver Hans Richter Jean-Marc Plancher Jacques Mizrahi Craig S. Malcolm Antony R. Knight Guy A. Kennett Paul Hebeisen Ian A. Cliffe Anne Bourson Caterina Bissantz Jon M. Bentley Mike J. Bickerdike Agnès Bénardeau Steven P. Vickers |
| author_facet | David Adams Sven Taylor Stephan Röver Hans Richter Jean-Marc Plancher Jacques Mizrahi Craig S. Malcolm Antony R. Knight Guy A. Kennett Paul Hebeisen Ian A. Cliffe Anne Bourson Caterina Bissantz Jon M. Bentley Mike J. Bickerdike Agnès Bénardeau Steven P. Vickers |
| author_sort | David Adams |
| collection | DOAJ |
| description |
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.
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| first_indexed | 2024-04-12T06:00:24Z |
| format | Article |
| id | doaj.art-704809a7a0ca49da9c0163e20d7760c5 |
| institution | Directory Open Access Journal |
| issn | 0009-4293 2673-2424 |
| language | deu |
| last_indexed | 2024-04-12T06:00:24Z |
| publishDate | 2004-09-01 |
| publisher | Swiss Chemical Society |
| record_format | Article |
| series | CHIMIA |
| spelling | doaj.art-704809a7a0ca49da9c0163e20d7760c52022-12-22T03:45:03ZdeuSwiss Chemical SocietyCHIMIA0009-42932673-24242004-09-0158910.2533/0009429047776775065-HT2C Receptor Agonists for the Treatment of Obesity. Biological and Chemical AdventuresDavid AdamsSven TaylorStephan RöverHans RichterJean-Marc PlancherJacques MizrahiCraig S. MalcolmAntony R. KnightGuy A. KennettPaul HebeisenIan A. CliffeAnne BoursonCaterina BissantzJon M. BentleyMike J. BickerdikeAgnès BénardeauSteven P. Vickers 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. https://chimia.ch/chimia/article/view/3877ObesityPyrroloindole5-ht2c receptor agonistSulfamidate |
| spellingShingle | David Adams Sven Taylor Stephan Röver Hans Richter Jean-Marc Plancher Jacques Mizrahi Craig S. Malcolm Antony R. Knight Guy A. Kennett Paul Hebeisen Ian A. Cliffe Anne Bourson Caterina Bissantz Jon M. Bentley Mike J. Bickerdike Agnès Bénardeau Steven P. Vickers 5-HT2C Receptor Agonists for the Treatment of Obesity. Biological and Chemical Adventures CHIMIA Obesity Pyrroloindole 5-ht2c receptor agonist Sulfamidate |
| title | 5-HT2C Receptor Agonists for the Treatment of Obesity. Biological and Chemical Adventures |
| title_full | 5-HT2C Receptor Agonists for the Treatment of Obesity. Biological and Chemical Adventures |
| title_fullStr | 5-HT2C Receptor Agonists for the Treatment of Obesity. Biological and Chemical Adventures |
| title_full_unstemmed | 5-HT2C Receptor Agonists for the Treatment of Obesity. Biological and Chemical Adventures |
| title_short | 5-HT2C Receptor Agonists for the Treatment of Obesity. Biological and Chemical Adventures |
| title_sort | 5 ht2c receptor agonists for the treatment of obesity biological and chemical adventures |
| topic | Obesity Pyrroloindole 5-ht2c receptor agonist Sulfamidate |
| url | https://chimia.ch/chimia/article/view/3877 |
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