Synthesis and SAR of 2,3,3a,4-tetrahydro-1H-pyrrolo[3,4-c]isoquinolin-5(9bH)-ones as 5-HT2C receptor agonists

• Published in: Bioorganic & medicinal chemistry letters Vol. 23; no. 1; pp. 330 - 335
• Main Authors: Fevig, John M., Feng, Jianxin, Rossi, Karen A., Miller, Keith J., Wu, Ginger, Hung, Chen-Pin, Ung, Thao, Malmstrom, Sarah E., Zhang, Ge, Keim, William J., Cullen, Mary Jane, Rohrbach, Kenneth W., Qu, Qinling, Gan, Jinping, Pelleymounter, Mary Ann, Robl, Jeffrey A.
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 01.01.2013; Elsevier
• Subjects: 5-HT2c receptor agonist; agonistic behavior; agonists; Animals; Chemistry; Chemistry, Medicinal; Chemistry, Organic; food intake; Half-Life; Heterocyclic Compounds, 3-Ring - chemical synthesis; Heterocyclic Compounds, 3-Ring - chemistry; Heterocyclic Compounds, 3-Ring - pharmacokinetics; Humans; Isoquinolines - chemical synthesis; Isoquinolines - chemistry; Isoquinolines - pharmacokinetics; Life Sciences & Biomedicine; Male; Obesity; Pharmacology & Pharmacy; Physical Sciences; Pyrroles - chemical synthesis; Pyrroles - chemistry; Pyrroles - pharmacokinetics; Rats; Rats, Sprague-Dawley; Receptor, Serotonin, 5-HT2A - chemistry; Receptor, Serotonin, 5-HT2A - metabolism; Receptor, Serotonin, 5-HT2B - chemistry; Receptor, Serotonin, 5-HT2B - metabolism; Receptor, Serotonin, 5-HT2C - chemistry; Receptor, Serotonin, 5-HT2C - metabolism; receptors; Science & Technology; Serotonin; Serotonin 5-HT2 Receptor Agonists - chemical synthesis; Serotonin 5-HT2 Receptor Agonists - chemistry; Serotonin 5-HT2 Receptor Agonists - pharmacokinetics; Structure-Activity Relationship; Serotonin; Obesity; 5-HT2c receptor agonist; LORCASERIN; MICE; FENFLURAMINE; DISCOVERY
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2012.10.091

A series of 2,3,3a,4-tetrahydro-1H-pyrrolo[3,4-c]isoquinolin-5(9bH)-ones is described, several examples of which exhibit potent 5-HT2C agonism with excellent selectivity over the closely related 5-HT2A and 5-HT2B receptors. Compounds such as 38 and 44 were shown to be effective in reducing food intake in an acute rat feeding model. A series of 2,3,3a,4-tetrahydro-1H-pyrrolo[3,4-c]isoquinolin-5(9bH)-ones is described, several examples of which exhibit potent 5-HT2C agonism with excellent selectivity over the closely related 5-HT2A and 5-HT2B receptors. Compounds such as 38 and 44 were shown to be effective in reducing food intake in an acute rat feeding model.