title: 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.
abstract: 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.
authors.affiliation: Evotec UK Ltd, 114 Milton Park, Abingdon, Oxfordshire OX14 4SA, UK. heather.tye@evotec.com
authors.forename: Heather
authors.initials: H
authors.lastname: Tye
authors.forename: Stephan G
authors.initials: SG
authors.lastname: Mueller
authors.forename: Juergen
authors.initials: J
authors.lastname: Prestle
authors.forename: Stefan
authors.initials: S
authors.lastname: Scheuerer
authors.forename: Marcus
authors.initials: M
authors.lastname: Schindler
authors.forename: Bernd
authors.initials: B
authors.lastname: Nosse
authors.forename: Natacha
authors.initials: N
authors.lastname: Prevost
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Brown
authors.forename: Alexander
authors.initials: A
authors.lastname: Heifetz
authors.forename: Clemens
authors.initials: C
authors.lastname: Moeller
authors.forename: Anna
authors.initials: A
authors.lastname: Pedret-Dunn
authors.forename: Mark
authors.initials: M
authors.lastname: Whittaker
mesh_terms: D000818:Animals; D001372:Aza Compounds / Q000737:chemistry; D001381:Azepines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors / Q000378:metabolism; D006575:Heterocyclic Compounds, 3-Ring / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D006801:Humans; D007192:Indenes / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D008297:Male; D008659:Metabolic Diseases / Q000188:drug therapy*; D011743:Pyrimidines / Q000737:chemistry; D051381:Rats; D017208:Rats, Wistar; D044402:Receptor, Serotonin, 5-HT2A / Q000737:chemistry / Q000378:metabolism; D044403:Receptor, Serotonin, 5-HT2B / Q000737:chemistry / Q000378:metabolism; D044405:Receptor, Serotonin, 5-HT2C / Q000737:chemistry* / Q000378:metabolism; D058826:Serotonin 5-HT2 Receptor Agonists / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D013329:Structure-Activity Relationship
chemical_list: D001372:Aza Compounds; D001381:Azepines; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D006575:Heterocyclic Compounds, 3-Ring; D007192:Indenes; C000606913:KCNH2 protein, human; D011743:Pyrimidines; D044402:Receptor, Serotonin, 5-HT2A; D044403:Receptor, Serotonin, 5-HT2B; D044405:Receptor, Serotonin, 5-HT2C; D058826:Serotonin 5-HT2 Receptor Agonists; C030986:pyrimidine