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
  • 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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