ABSTRACT
Hepatitis C represents a serious worldwide health-care problem. Recently, we have disclosed a novel class of P2-P4 macrocyclic inhibitors of NS3/4A protease containing a carbamate functionality as capping group at the P3 N-terminus. Herein we report our work aimed at further depeptidizing the P3 region by replacement of the urethane function with a succinamide motif. This peptidomimetic approach has led to the discovery of novel P2-P4 macrocyclic inhibitors of HCV NS3/4A protease with sub-nanomolar enzyme affinities. In addition to being potent inhibitors of HCV subgenomic replication, optimized analogues within this series have also presented attractive PK properties and showed promising liver levels in rat following oral administration.
Subject(s)
Antiviral Agents/chemistry , Protease Inhibitors/chemistry , Viral Nonstructural Proteins/antagonists & inhibitors , Administration, Oral , Amides/chemistry , Animals , Antiviral Agents/chemical synthesis , Antiviral Agents/pharmacokinetics , Binding Sites , Cell Line , Computer Simulation , Cyclopropanes , Humans , Indoles/chemistry , Indoles/pharmacokinetics , Isoindoles , Lactams, Macrocyclic , Leucine/analogs & derivatives , Proline/analogs & derivatives , Protease Inhibitors/chemical synthesis , Protease Inhibitors/pharmacokinetics , Rats , Rats, Wistar , Succinates , Sulfonamides , Viral Nonstructural Proteins/metabolismABSTRACT
Infections caused by the hepatitis C virus (HCV) are a significant world health problem for which novel therapies are in urgent demand. The NS5B polymerase of HCV is responsible for the replication of viral RNA and has been a prime target in the search for novel treatment options. We had discovered allosteric finger-loop inhibitors based on a thieno[3,2-b]pyrrole scaffold as an alternative to the related indole inhibitors. Optimization of the thienopyrrole series led to several N-acetamides with submicromolar potency in the cell-based replicon assay, but they lacked oral bioavailability in rats. By linking the N4-position to the ortho-position of the C5-aryl group, we were able to identify the tetracyclic thienopyrrole 40, which displayed a favorable pharmacokinetic profile in rats and dogs and is equipotent with recently disclosed finger-loop inhibitors based on an indole scaffold.
