Structure-activity relationship of pyrrole based S-nitrosoglutathione reductase inhibitors: carboxamide modification

Bioorg Med Chem Lett. 2012 Mar 15;22(6):2338-42. doi: 10.1016/j.bmcl.2012.01.047. Epub 2012 Feb 2.

Abstract

The enzyme S-nitrosoglutathione reductase (GSNOR) is a member of the alcohol dehydrogenase family (ADH) that regulates the levels of S-nitrosothiols (SNOs) through catabolism of S-nitrosoglutathione (GSNO). GSNO and SNOs are implicated in the pathogenesis of many diseases including those in respiratory, gastrointestinal, and cardiovascular systems. The pyrrole based N6022 was recently identified as a potent, selective, reversible, and efficacious GSNOR inhibitor which is currently in clinical development for acute asthma. We describe here the synthesis and structure-activity relationships (SAR) of novel pyrrole based analogs of N6022 focusing on carboxamide modifications on the pendant N-phenyl moiety. We have identified potent and novel GSNOR inhibitors that demonstrate efficacy in an ovalbumin (OVA) induced asthma model in mice.

MeSH terms

  • Acute Disease
  • Aldehyde Oxidoreductases / antagonists & inhibitors*
  • Aldehyde Oxidoreductases / metabolism
  • Animals
  • Anti-Asthmatic Agents / administration & dosage
  • Anti-Asthmatic Agents / chemical synthesis*
  • Anti-Asthmatic Agents / therapeutic use
  • Asthma / chemically induced
  • Asthma / drug therapy*
  • Asthma / enzymology
  • Benzamides / administration & dosage
  • Benzamides / chemical synthesis*
  • Benzamides / therapeutic use
  • Enzyme Inhibitors / administration & dosage
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / therapeutic use
  • Humans
  • Male
  • Mice
  • Ovalbumin
  • Pyrroles / administration & dosage
  • Pyrroles / chemical synthesis*
  • Pyrroles / therapeutic use
  • S-Nitrosoglutathione / metabolism
  • S-Nitrosothiols / metabolism
  • Structure-Activity Relationship

Substances

  • Anti-Asthmatic Agents
  • Benzamides
  • Enzyme Inhibitors
  • N6022
  • Pyrroles
  • S-Nitrosothiols
  • S-Nitrosoglutathione
  • Ovalbumin
  • Aldehyde Oxidoreductases
  • formaldehyde dehydrogenase, glutathione-independent