Novel and Selective 5-HT 2C/2B Receptor Antagonists as Potential Anxiolytic Agents: Synthesis, Quantitative Structure−Activity Relationships, and Molecular Modeling of Substituted 1-(3-Pyridylcarbamoyl)indolines
1998; American Chemical Society; Volume: 41; Issue: 10 Linguagem: Inglês
10.1021/jm970741j
ISSN1520-4804
AutoresSteven M. Bromidge, Steven Dabbs, David T. Davies, D. Malcolm Duckworth, Ian T. Forbes, P. J. Ham, Graham E. Jones, Frank D. King, Damian V. Saunders, Susannah Starr, Kevin M. Thewlis, Paul Wyman, Frank E. Blaney, Christopher Naylor, Fiona P. Bailey, Thomas P. Blackburn, Vicky Holland, G.A. Kennett, Graham J. Riley, Martyn Wood,
Tópico(s)Cyclopropane Reaction Mechanisms
ResumoThe 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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