Biarylcarbamoylindolines are novel and selective 5-HT(2C) receptor inverse agonists: identification of 5-methyl-1-[[2-[(2-methyl-3-pyridyl)oxy]- 5-pyridyl]carbamoyl]-6-trifluoromethylindoline (SB-243213) as a potential antidepressant/anxiolytic agent

• Published in: Journal of medicinal chemistry Vol. 43; no. 6; pp. 1123 - 1134
• Main Authors: Bromidge, S M, Dabbs, S, Davies, D T, Davies, S, Duckworth, D M, Forbes, I T, Gaster, L M, Ham, P, Jones, G E, King, F D, Mulholland, K R, Saunders, D V, Wyman, P A, Blaney, F E, Clarke, S E, Blackburn, T P, Holland, V, Kennett, G A, Lightowler, S, Middlemiss, D N, Trail, B, Riley, G J, Wood, M D
• Format: Journal Article
• Language: English
• Published: United States 23.03.2000
• Subjects: Administration, Oral; Animals; Anti-Anxiety Agents - chemical synthesis; Anti-Anxiety Agents - chemistry; Anti-Anxiety Agents - metabolism; Anti-Anxiety Agents - pharmacology; Antidepressive Agents - chemical synthesis; Antidepressive Agents - chemistry; Antidepressive Agents - metabolism; Antidepressive Agents - pharmacology; Cell Line; Humans; Indoles - chemical synthesis; Indoles - chemistry; Indoles - metabolism; Indoles - pharmacology; Models, Molecular; Motor Activity - drug effects; Pyridines - chemical synthesis; Pyridines - chemistry; Pyridines - metabolism; Pyridines - pharmacology; Radioligand Assay; Rats; Receptor, Serotonin, 5-HT2A; Receptor, Serotonin, 5-HT2B; Receptor, Serotonin, 5-HT2C; Receptors, Serotonin - metabolism; Serotonin Receptor Agonists - chemical synthesis; Serotonin Receptor Agonists - chemistry; Serotonin Receptor Agonists - metabolism; Serotonin Receptor Agonists - pharmacology; Structure-Activity Relationship
• ISSN: 0022-2623
• DOI: 10.1021/jm990388c

The evolution, synthesis, and biological activity of a novel series of 5-HT(2C) receptor inverse agonists are reported. Biarylcarbamoylindolines have been identified with excellent 5-HT(2C) affinity and selectivity over 5-HT(2A) receptors. In addition, (pyridyloxypyridyl)carbamoylindolines have been discovered with additional selectivity over the closely related 5-HT(2B) receptor. Compounds from this series are inverse agonists at the human cloned 5-HT(2C) receptor, completely abolishing basal activity in a functional assay. The new series have reduced P450 inhibitory liability compared to a previously described series of 1-(3-pyridylcarbamoyl)indolines (Bromidge et al. J. Med. Chem. 1998, 41, 1598) from which they evolved. Compounds from this series showed excellent oral activity in a rat mCPP hypolocomotion model and in animal models of anxiety. On the basis of their favorable biological profile, 32 (SB-228357) and 40 (SB-243213) have been selected for further evaluation to determine their therapeutic potential for the treatment of CNS disorders such as depression and anxiety.