264617-07-4Relevant articles and documents
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
Bromidge, Steven M.,Dabbs, Steven,Davies, David T.,Davies, Susannah,Duckworth, D. Malcolm,Forbes, Ian T.,Gaster, Laramie M.,Ham, Peter,Jones, Graham E.,King, Frank D.,Mulholland, Keith R.,Saunders, Damian V.,Wyman, Paul A.,Blaney, Frank E.,Clarke, Stephen E.,Blackburn, Thomas P.,Holland, Vicky,Kennett, Guy A.,Lightowler, Sean,Middlemiss, Derek N.,Trail, Brenda,Riley, Graham J.,Wood, Martyn D.
, p. 1123 - 1134 (2007/10/03)
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.
