Design and synthesis of a candidate α-human thrombin irreversible inhibitor containing a hydrophobic carborane pharmacophore

alpha-Human thrombin is a potent platelet agonist involved in the blood coagulation cascade and is an attractive target for an anticoagulant agent due to its involvement in several debilitating diseases. In this contribution we present attempts to develop a new architecture for size-selective serine protease inhibitors that utilize a fully methylated icosahedral p-carborane as a dominating hydrophobic pharmacophore. Using a computational docking program, flexX, a carborane-containing inhibitor was designed and synthesized. Computationally, this compound displayed the ability to provide ligand-protein binding interactions throughout the thrombin's main active site (S1-S3), while positioning an acylating group for facile irreversible attack at the Ser(195) hydroxyl group.