P4 capped amides and lactams as HCV NS3 protease inhibitors with improved potency and DMPK profile

Bioorg Med Chem Lett. 2010 Jan 15;20(2):567-70. doi: 10.1016/j.bmcl.2009.11.094. Epub 2009 Nov 22.

Abstract

SAR studies on the extension of P3 unit of Boceprevir (1, SCH 503034) with amides and lactams and their synthesis is described. Extensive SAR studies resulted in the identification of 36 bearing 4, 4-dimethyl lactam as the new P4 cap unit with improved potency (K(i)( *)=15nM, EC 90=70nM) and pharmacokinetic properties (Rat AUC (PO)=3.52microMh) compared to 1.

MeSH terms

  • Amides / chemical synthesis
  • Amides / chemistry*
  • Amides / pharmacokinetics
  • Animals
  • Antiviral Agents / chemical synthesis
  • Antiviral Agents / chemistry*
  • Antiviral Agents / pharmacokinetics
  • Binding Sites
  • Crystallography, X-Ray
  • Lactams / chemical synthesis
  • Lactams / chemistry*
  • Lactams / pharmacokinetics
  • Oligopeptides / chemical synthesis
  • Oligopeptides / chemistry*
  • Oligopeptides / pharmacokinetics
  • Proline / analogs & derivatives
  • Proline / chemistry
  • Proline / pharmacokinetics
  • Protease Inhibitors / chemical synthesis
  • Protease Inhibitors / chemistry*
  • Protease Inhibitors / pharmacokinetics
  • Rats
  • Structure-Activity Relationship
  • Viral Nonstructural Proteins / antagonists & inhibitors*
  • Viral Nonstructural Proteins / metabolism

Substances

  • Amides
  • Antiviral Agents
  • Lactams
  • NS3 protein, hepatitis C virus
  • Oligopeptides
  • Protease Inhibitors
  • Viral Nonstructural Proteins
  • N-(3-amino-1-(cyclobutylmethyl)-2,3-dioxopropyl)-3-(2-((((1,1-dimethylethyl)amino)carbonyl)amino)-3,3-dimethyl-1-oxobutyl)-6,6-dimethyl-3-azabicyclo(3.1.0)hexan-2-carboxamide
  • Proline

Associated data

  • PDB/3KN2