2. Academic Validation
  3. 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

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

  • J Med Chem. 2000 Mar 23;43(6):1123-34. doi: 10.1021/jm990388c.
S M Bromidge 1,  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
Affiliations

Affiliation

  • 1 SmithKline Beecham Pharmaceuticals, Discovery Research, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, UK. [email protected]
PMID: 10737744 DOI: 10.1021/jm990388c
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.

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