Inhibition of human neutrophil elastase. 4. Design, synthesis, X-ray crystallographic analysis, and structure-activity relationships for a series of P2-modified, orally active peptidyl pentafluoroethyl ketones

J Med Chem. 1998 Jul 2;41(14):2461-80. doi: 10.1021/jm970812e.

Abstract

A series of P2-modified, orally active peptidic inhibitors of human neutrophil elastase (HNE) are reported. These pentafluoroethyl ketone-based inhibitors were designed using pentafluoroethyl ketone 1 as a model. Rational structural modifications were made at the P3, P2, and activating group (AG) portions of 1 based on structure-activity relationships (SAR) developed from in vitro (measured Ki) data and information provided by modeling studies that docked inhibitor 1 into the active site of HNE. The modeling-based design was corroborated with X-ray crystallographic analysis of the complex between 1 and porcine pancreatic elastase (PPE) and subsequently the complex between 1 and HNE.

MeSH terms

  • Administration, Oral
  • Animals
  • Azetidines / chemistry
  • Binding Sites
  • Cricetinae
  • Crystallography, X-Ray
  • Drug Design*
  • Fluorocarbons / chemistry
  • Fluorocarbons / metabolism
  • Fluorocarbons / pharmacology
  • Hemorrhage / chemically induced
  • Hemorrhage / enzymology
  • Hemorrhage / prevention & control
  • Humans
  • Isoquinolines / chemistry
  • Ketones* / chemical synthesis
  • Ketones* / chemistry
  • Ketones* / metabolism
  • Ketones* / pharmacology
  • Leukocyte Elastase / antagonists & inhibitors*
  • Leukocyte Elastase / metabolism
  • Lung Diseases / chemically induced
  • Lung Diseases / enzymology
  • Lung Diseases / prevention & control
  • Models, Molecular
  • Molecular Conformation
  • Neutrophils / enzymology*
  • Oligopeptides* / chemical synthesis
  • Oligopeptides* / chemistry
  • Oligopeptides* / metabolism
  • Oligopeptides* / pharmacology
  • Pancreatic Elastase / antagonists & inhibitors
  • Pancreatic Elastase / metabolism
  • Proline / analogs & derivatives
  • Proline / chemistry
  • Serine Proteinase Inhibitors* / chemical synthesis
  • Serine Proteinase Inhibitors* / chemistry
  • Serine Proteinase Inhibitors* / metabolism
  • Serine Proteinase Inhibitors* / pharmacology
  • Structure-Activity Relationship
  • Swine

Substances

  • Azetidines
  • Fluorocarbons
  • Isoquinolines
  • Ketones
  • Oligopeptides
  • Serine Proteinase Inhibitors
  • azetidine
  • Proline
  • homoproline
  • Pancreatic Elastase
  • Leukocyte Elastase
  • isoquinoline