Rational design and synthesis towards alpha human thrombin inhibitors containing a hydrophobic carborane pharmacophore

Alpha human thrombin is a potent platelet agonist involved in the blood coagulation cascade that represents an attractive target for an anticoagulant due to its involvement in several debilitating diseases. Herein are presented efforts to develop a new class of potent and selective serine protease inhibitors that utilize a substituted icosahedral carborane as a hydrophobic pharmacophore. Using a computation docking program FLEXX and structure analysis relationship (SAR) studies several potential inhibitors were designed and synthesized that computationally demonstrated the ability to extend favorable ligand-protein-binding interactions throughout the main regions of the protein active site (S1-S3).