Novel and Selective 5-HT<INF>2C/2B</INF> Receptor Antagonists as Potential Anxiolytic Agents:  Synthesis, Quantitative Structure−Activity Relationships, and Molecular Modeling of Substituted 1-(3-Pyridylcarbamoyl)indolines

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 <BO>1 </BO>(SB-206553) and illustrate the use of aromatic disubstitution as a replacement for fused five-membered rings in the context of 5-HT<INF>2C/2B</INF> receptor antagonists. By targeting a region of space previously identified as sterically allowed at the 5-HT<INF>2C</INF> receptor but disallowed at the 5-HT<INF>2A</INF> receptor, we have identified a number of compounds which are the most potent and selective 5-HT<INF>2C/2B</INF> receptor antagonists yet reported. <BO>46</BO> (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-HT<INF>2C</INF> receptor model and our proposed binding mode for this class of ligands within that model.