Inhibition of the tissue factor/factor VIIa complex — Lead optimisation using combinatorial chemistry

Abstract

Following a high throughput screen (HTS) for the inhibition of the tissue factor/factor VIIa complex and the identification of a number of original hits a lead optimisation programme was initiated to improve their potency. This necessitated the development of an amidine based linker which allowed the generation of a library of amidinonaphthols prepared both by multiple parallel synthesis (MPS) and split and mix methods. The most active compound had an IC 50 of 4μM some 10x more potent than the original lead compound.