ABSTRACT
Exploration of the P2 region by mimicking the proline motif found in BILN2061 resulted in the discovery of two series of potent HCV NS3/4A protease inhibitors. X-ray crystal structure of the ligand in contact with the NS3/4A protein and modulation of the quinoline heterocyclic region by structure based design and modeling allowed for the optimization of enzyme potency and cellular activity. This research led to the selection of clinical candidate IDX320 having good genotype coverage and pharmacokinetic properties in various species.
Subject(s)
Drug Discovery , Hepacivirus/drug effects , Macrocyclic Compounds/chemistry , Macrocyclic Compounds/pharmacology , Viral Nonstructural Proteins/antagonists & inhibitors , Animals , Haplorhini , Hepatocytes/enzymology , Humans , Inhibitory Concentration 50 , Mice , Microsomes, Liver/enzymology , Molecular Structure , Rats , Rats, Sprague-Dawley , Serine Proteinase Inhibitors/chemical synthesis , Serine Proteinase Inhibitors/chemistry , Serine Proteinase Inhibitors/pharmacology , Viral Nonstructural Proteins/chemistryABSTRACT
A norbornene-mediated palladium-catalyzed tandem alkylation/cyanation sequence is described in which an alkyl-aryl bond and a nitrile-aryl bond are formed in one pot. A variety of sterically hindered, five-, six-, and seven-membered ring benzonitriles were synthesized in good yields from easily accessible starting materials.
