2. Academic Validation
  3. Novel and selective 5-HT2C/2B receptor antagonists as potential anxiolytic agents: synthesis, quantitative structure-activity relationships, and molecular modeling of substituted 1-(3-pyridylcarbamoyl)indolines

Novel and selective 5-HT2C/2B receptor antagonists as potential anxiolytic agents: synthesis, quantitative structure-activity relationships, and molecular modeling of substituted 1-(3-pyridylcarbamoyl)indolines

  • J Med Chem. 1998 May 7;41(10):1598-612. doi: 10.1021/jm970741j.
S M Bromidge 1,  S Dabbs,  D T Davies,  D M Duckworth,  I T Forbes,  P Ham,  G E Jones,  F D King,  D V Saunders,  S Starr,  K M Thewlis,  P A Wyman,  F E Blaney,  C B Naylor,  F Bailey,  T P Blackburn,  V Holland,  G A Kennett,  G J Riley,  M D Wood
Affiliations

Affiliation

  • 1 SmithKline Beecham Pharmaceuticals, Discovery Research, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, England.
PMID: 9572885 DOI: 10.1021/jm970741j
Abstract

The synthesis, biological activity, and molecular modeling of a novel series of substituted 1-(3-pyridylcarbamoyl)indolines are reported. These compounds are isosteres of the previously published indole urea 1 (SB-206553) and illustrate the use of aromatic disubstitution as a replacement for fused five-membered rings in the context of 5-HT2C/2B receptor antagonists. By targeting a region of space previously identified as sterically allowed at the 5-HT2C receptor but disallowed at the 5-HT2A receptor, we have identified a number of compounds which are the most potent and selective 5-HT2C/2B receptor antagonists yet reported. 46 (SB-221284) was selected on the basis of its overall biological profile for further evaluation as a novel, potential nonsedating anxiolytic agent. A CoMFA analysis of these compounds produced a model with good predictive value and in addition good qualitative agreement with both our 5-HT2C receptor model and our proposed binding mode for this class of ligands within that model.

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