Novel 6,7,8,9-tetrahydro-5H-1,4,7,10a-tetraaza-cyclohepta[f]indene analogues as potent and selective 5-HT2C agonists for the treatment of metabolic disorders
✍ Scribed by Heather Tye; Stephan G. Mueller; Juergen Prestle; Stefan Scheuerer; Marcus Schindler; Bernd Nosse; Natacha Prevost; Christopher J. Brown; Alexander Heifetz; Clemens Moeller; Anna Pedret-Dunn; Mark Whittaker
- Publisher
- Elsevier Science
- Year
- 2011
- Tongue
- English
- Weight
- 338 KB
- Volume
- 21
- Category
- Article
- ISSN
- 0960-894X
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✦ Synopsis
The discovery of a novel series of 5-HT(2C) agonists based on a tricyclic pyrazolopyrimidine scaffold is described. Compounds with good levels of in vitro potency and moderate to good levels of selectivity with respect to the 5-HT(2A) and 5-HT(2B) receptors were identified. One of the analogues (7 g) was found to be efficacious in a sub-chronic weight loss model. A key limitation of the series of compounds was that they were found to be potent inhibitors of the hERG ion channel. Some compounds, bearing polar side chains were identified which showed a much reduced hERG liability however these compounds were sub-optimal in terms of their in vitro potency or selectivity.