Synthesis and elastase-inhibiting activity of 2-pyridinyl-isothiazol-3(2H)-one 1,1-dioxides

Bioorg Med Chem. 2008 Sep 1;16(17):8127-35. doi: 10.1016/j.bmc.2008.07.049. Epub 2008 Jul 24.

Abstract

The synthesis of a series of new isothiazol-3(2H)-one 1,1-dioxides with halogenated (mostly fluorinated) pyridinyl and pentafluorophenyl substituents at 2-position is reported. These compounds (18-24) became easily accessible from 2-thiocyanato-1-carboxaldehydes and aminopyridines, pentafluoroaniline, respectively, by an isothiazolium cyclization-oxidation route. Compound 21 exhibited an IC(50) value of 3.1 microM toward human leukocyte elastase. The proteases cathepsin G, trypsin, cathepsin L, and angiotensin-converting enzyme, and the serine esterases acetylcholinesterase and cholesterol esterase were not inhibited by 21.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcholinesterase / drug effects
  • Cathepsin G
  • Cathepsin L
  • Cathepsins / antagonists & inhibitors
  • Crystallography, X-Ray
  • Cyclic S-Oxides / chemical synthesis*
  • Cyclic S-Oxides / chemistry
  • Cyclic S-Oxides / pharmacology*
  • Cyclization
  • Cysteine Endopeptidases
  • Dose-Response Relationship, Drug
  • Drug Evaluation, Preclinical
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Leukocyte Elastase / antagonists & inhibitors*
  • Models, Molecular
  • Molecular Structure
  • Oxidation-Reduction
  • Peptidyl-Dipeptidase A / drug effects
  • Serine Endopeptidases
  • Stereoisomerism
  • Sterol Esterase / antagonists & inhibitors
  • Structure-Activity Relationship
  • Trypsin / drug effects

Substances

  • Cyclic S-Oxides
  • Enzyme Inhibitors
  • Sterol Esterase
  • Acetylcholinesterase
  • Cathepsins
  • ACE protein, human
  • Peptidyl-Dipeptidase A
  • Serine Endopeptidases
  • CTSG protein, human
  • Cathepsin G
  • Leukocyte Elastase
  • Trypsin
  • Cysteine Endopeptidases
  • CTSL protein, human
  • Cathepsin L