The successful quest for oral factor Xa inhibitors; learnings for all of medicinal chemistry?

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. (C) 2011 Elsevier Ltd. All rights reserved.