ABSTRACT
[reaction: see text] In this, the first of two Letters, we describe how a P3/P4 urea linking unit was used to greatly enhance the biochemical and replicon potency of inhibitors based upon the pyrrolidine-5,5-trans-lactam template. Compound 7b demonstrated a 100 nM IC(50) in the replicon cell-based surrogate HCV assay.
Subject(s)
Antiviral Agents/chemical synthesis , Hepacivirus/enzymology , Lactams/chemistry , Protease Inhibitors/chemical synthesis , Pyrrolidines/chemistry , Urea/chemistry , Viral Nonstructural Proteins/antagonists & inhibitors , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Crystallography, X-Ray , Hepacivirus/drug effects , Hepacivirus/physiology , Inhibitory Concentration 50 , Molecular Conformation , Molecular Structure , Protease Inhibitors/chemistry , Protease Inhibitors/pharmacology , Viral Nonstructural Proteins/metabolism , Virus Replication/drug effectsABSTRACT
[reaction: see text] In this, the first of two letters, we outline the use of the pyrrolidine-5,5-trans-lactam template to design small, neutral, mechanism-based inhibitors of hepatitis C NS3/4A protease. The hitherto unreported reaction of the acyl iminium ion precursor 4 with dialkyl-substituted silyl ketene acetals (e.g., 8b) is described. Compound 12b, with a spirocyclobutyl P1 substituent and a cyclopropylacyl substituent on the lactam nitrogen, has a k(obs)/I of 400 M(-)(1) s(-)(1) and demonstrates activity in a replicon cell-based surrogate HCV assay.
Subject(s)
Hepacivirus/enzymology , Lactams/chemical synthesis , Protease Inhibitors/chemical synthesis , Protease Inhibitors/pharmacology , Pyrrolidines/chemical synthesis , Serine Endopeptidases/metabolism , Viral Nonstructural Proteins/antagonists & inhibitors , Cell Line , Drug Design , Drug Stability , Hepacivirus/drug effects , Humans , Lactams/chemistry , Molecular Structure , Protease Inhibitors/chemistry , Pyrrolidines/chemistry , Viral Nonstructural Proteins/metabolismABSTRACT
Using a pyrrolidine-5,5-trans-lactam template, we have designed small, neutral, mechanism-based inhibitors of hepatitis C NS3/4A protease. Compound 11a, with an alpha-ethyl P1 substituent and a Boc-valine substituent at the pyrrolidine nitrogen, has an IC(50)=30 microM.