Bromidge S M, Dabbs S, Davies D T, Duckworth D M, Forbes I T, Ham P, Jones G E, King F D, Saunders D V, Starr S, Thewlis K M, Wyman P A, Blaney F E, Naylor C B, Bailey F, Blackburn T P, Holland V, Kennett G A, Riley G J, Wood M D
SmithKline Beecham Pharmaceuticals, Discovery Research, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, England.
J Med Chem. 1998 May 7;41(10):1598-612. doi: 10.1021/jm970741j.
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.
报道了一系列新型取代的1-(3-吡啶甲酰基)吲哚啉的合成、生物活性及分子模拟。这些化合物是先前报道的吲哚脲1（SB - 206553）的电子等排体，说明了在5 - HT2C/2B受体拮抗剂的背景下，芳基二取代作为稠合五元环替代物的应用。通过靶向先前确定在5 - HT2C受体空间上允许但在5 - HT2A受体上不允许的区域，我们已鉴定出一些化合物，它们是迄今报道的最有效和最具选择性的5 - HT2C/2B受体拮抗剂。基于其整体生物学特性，选择了46（SB - 221284）作为一种新型潜在非镇静抗焦虑剂进行进一步评估。对这些化合物的比较分子场分析产生了一个具有良好预测价值的模型，并且在定性上与我们的5 - HT2C受体模型以及我们在此模型中提出的此类配体的结合模式均有良好的一致性。
