| Literature DB >> 10737744 |
S M Bromidge1, S Dabbs, D T Davies, S Davies, D M Duckworth, I T Forbes, L M Gaster, P Ham, G E Jones, F D King, K R Mulholland, D V Saunders, P A Wyman, F E Blaney, S E Clarke, T P Blackburn, V Holland, G A Kennett, S Lightowler, D N Middlemiss, B Trail, G J Riley, M D Wood.
Abstract
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.Entities:
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Year: 2000 PMID： 10737744 DOI： 10.1021/jm990388c
Source DB: PubMed Journal: J Med Chem ISSN： 0022-2623 Impact factor: 7.446