Design and Synthesis of a Candidate α-Human Thrombin Irreversible ­Inhibitor Containing a Hydrophobic Carborane Pharmacophore

Abstract

S y n t h e s i s o f a C a n d i d a t e a -H u m a n T h r o m b i n I r r e v e r s i b l e I n h i b i t o rAbstract: a-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.

Carborane-Containing Hydroxamate MMP Ligands for the Treatment of Tumors Using Boron Neutron Capture Therapy (BNCT): Efficacy without Tumor Cell Entry

“…Phenyl rings can act as bioisosteric replacements for carboranes, as can adamantane, due to their similarity in size and lipophilicity, which has been a practical approach to modeling and docking in medicinal chemistry [ 44 ]. There are a number of examples of closo-carboranes that have been used as bioisosteric replacements for heteroaromatic or heteroaliphatic rings [ 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 ]. As we have reported [ 32 ] for other MMP-targeting carborane-containing BNCT candidates, we employed an approach of replacing the carborane moiety with a phenyl ring for molecular docking experiments, given the similar 3-dimensional sweep volume and lipophilicity of both moieties.…”