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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
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
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
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.
Keywords:5HT2C agonist  Metabolic disease  hERG inhbiiton
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