Finger loop inhibitors of the HCV NS5b polymerase. Part II. Optimization of tetracyclic indole-based macrocycle leading to the discovery of TMC647055.

Abstract Optimization of a novel series of macrocyclic indole-based inhibitors of the HCV NS5b polymerase targeting the finger loop domain led to the discovery of lead compounds exhibiting improved potency in cellular assays and superior pharmacokinetic profile. Further lead optimization performed on the most promising unsaturated-bridged subseries provided the clinical candidate 27-cyclohexyl-12,13,16,17-tetrahydro-22-methoxy-11,17-dimethyl-10,10-dioxide-2,19-methano-3,7:4,1-dimetheno-1 H ,11 H -14,10,2,9,11,17-benzoxathiatetraazacyclo docosine-8,18(9 H ,15 H )-dione, TMC647055 (compound 18a ). This non-zwitterionic 17-membered ring macrocycle combines nanomolar cellular potency (EC 50 of 82 nM) with minimal associated cell toxicity (CC 50  >20 μM) and promising pharmacokinetic profiles in rats and dogs. TMC647055 is currently being evaluated in the clinic.