GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, United Kingdom.
Bioorg Med Chem Lett. 2011 Nov 1;21(21):6228-35. doi: 10.1016/j.bmcl.2011.08.119. Epub 2011 Sep 1.
The medicinal chemistry of oral small molecule factor Xa inhibitors is discussed, highlighting key advances that led to clinical candidates and the first licensed medicines. Identification of neutral ligands for the primary specificity pocket was a key discovery; capitalised upon by structure based design and combinatorial methods to deliver many variations on the theme; but it was good medicinal chemistry practice, in the optimisation of physical properties, which ultimately delivered efficacious compounds with adequate oral exposure. As a retrospective appraisal, representative compounds were profiled using the more contemporary concepts of Ligand Efficiency and Property Forecast Indices; which gave clear indications of the value of these principles.
本文讨论了口服小分子 Xa 因子抑制剂的药物化学，重点介绍了导致临床候选药物和首个获批药物的关键进展。识别主要特异性口袋的中性配体是一项关键发现；基于结构的设计和组合方法利用这一发现，衍生出了许多变体；但在优化物理性质方面的良好药物化学实践最终提供了具有足够口服暴露量的有效化合物。作为回顾性评估，使用更现代的配体效率和性质预测指数概念对代表性化合物进行了剖析；这些概念清楚地表明了这些原则的价值。
