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

• Published in: Bioorganic & medicinal chemistry letters Vol. 21; no. 1; pp. 34 - 37
• Main 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
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 01.01.2011; Elsevier
• Subjects: 5HT2C agonist; agonists; Biological and medical sciences; chemistry; General and cellular metabolism. Vitamins; hERG inhbiiton; ion channels; Medical sciences; Metabolic disease; metabolic diseases; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Pharmacology. Drug treatments; receptors; Serotoninergic system; weight loss; 5HT2C agonist; Metabolic disease; hERG inhbiiton; Agonist; Rat; Toxicity; Rodentia; Metabolic diseases; Ionic channel; Selectivity; In vitro; In vivo; Vertebrata; Metabolic disorder; Mammalia; Treatment; Structure activity relation; Animal; Azetidine derivatives; Circulatory system; Pharmacokinetics; 5-HT2C serotonin receptor; Lipophilicity; Physicochemical properties
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2010.11.089

A new class of potent and selective 5-HT2C agonists for the treatment of metabolic disorders is described. Optimization of selectivity, permeability and hERG interaction is discussed. 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.