Novel 6,7,8,9-tetrahydro-5H-1,4,7,10a-tetraaza-cyclohepta[f]indene analogues as potent and selective 5-HT(2C) agonists for the treatment of metabolic disorders |
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Authors: | Tye Heather Mueller Stephan G Prestle Juergen Scheuerer Stefan Schindler Marcus Nosse Bernd Prevost Natacha Brown Christopher J Heifetz Alexander Moeller Clemens Pedret-Dunn Anna Whittaker Mark |
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Institution: | a Evotec (UK) Ltd, 114 Milton Park, Abingdon, Oxfordshire OX14 4SA, UK b Boehringer Ingelheim Pharma GmbH & Co. KG, Dept. Chemical Research, 88397 Biberach, Germany c Boehringer Ingelheim Pharma GmbH & Co. KG, Dept. Cardiometabolic Diseases Research, 88397 Biberach, Germany d Evotec AG, Schnackenburgallee 114, 22525 Hamburg, Germany e Boehringer Ingelheim Pharma GmbH & Co. KG, Dept. Drug Discovery Support, 88397 Biberach, Germany |
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Abstract: | The discovery of a novel series of 5-HT2C 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-HT2A and 5-HT2B receptors were identified. One of the analogues (7g) 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. |
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Keywords: | 5HT2C agonist Metabolic disease hERG inhbiiton |
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