Design, Synthesis, and Characterization of Dichlorobiphenyl-Derived Inhibitors of the Proprotein Convertase Furin

The proprotein convertase (PC) furin emerged as promising
drug
target for the treatment of numerous infectious diseases, cancer and
cystic fibrosis. A recently described nonpeptidic lead structure served
as template to develop a new series of PC inhibitors containing a
dichlorobiphenyl-derived core segment decorated with a left and right
inhibitor arm. The compounds were tested for their inhibitory potency
against furin and the structurally related PC7. The most potent compounds
inhibited furin with Ki values <5 nM,
whereas most of them were significantly weaker inhibitors of PC7.
Only for one compound, a significant potency with a Ki value of 7.3 nM against PC7 was found. Furthermore,
crystal structures of six inhibitors in complex with furin were determined.
Selected inhibitors were additionally tested for their antiviral potency
against the furin-dependent H7N7 influenza A strain SC35M; a significant
antiviral potency was found for compound 9.