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.
Copyright © 2012 Elsevier Ltd. All rights reserved.
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