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.
Subject(s)
Aldehyde Oxidoreductases/antagonists & inhibitors , Anti-Asthmatic Agents/chemical synthesis , Asthma/drug therapy , Benzamides/chemical synthesis , Enzyme Inhibitors/chemical synthesis , Pyrroles/chemical synthesis , Acute Disease , Aldehyde Oxidoreductases/metabolism , Animals , Anti-Asthmatic Agents/administration & dosage , Anti-Asthmatic Agents/therapeutic use , Asthma/chemically induced , Asthma/enzymology , Benzamides/administration & dosage , Benzamides/therapeutic use , Enzyme Inhibitors/administration & dosage , Enzyme Inhibitors/therapeutic use , Humans , Male , Mice , Ovalbumin , Pyrroles/administration & dosage , Pyrroles/therapeutic use , S-Nitrosoglutathione/metabolism , S-Nitrosothiols/metabolism , Structure-Activity RelationshipABSTRACT
The pyrrole based N6022 was recently identified as a potent, selective, reversible, and efficacious S-nitrosoglutathione reductase (GSNOR) inhibitor and is currently undergoing clinical development for the treatment of acute asthma. GSNOR is a member of the alcohol dehydrogenase family (ADH) and regulates the levels of S-nitrosothiols (SNOs) through catabolism of S-nitrosoglutathione (GSNO). Reduced levels of GSNO, as well as other nitrosothiols (SNOs), have been implicated in the pathogenesis of many diseases including those of the respiratory, cardiovascular, and gastrointestinal systems. Preservation of endogenous SNOs through GSNOR inhibition presents a novel therapeutic approach with broad applicability. We describe here the synthesis and structure-activity relationships (SAR) of novel pyrrole based analogues of N6022 focusing on removal of cytochrome P450 inhibition activities. We identified potent and novel GSNOR inhibitors having reduced CYP inhibition activities and demonstrated efficacy in a mouse ovalbumin (OVA) model of asthma.
Subject(s)
Aldehyde Oxidoreductases/antagonists & inhibitors , Benzamides/pharmacology , Cytochrome P-450 Enzyme System/metabolism , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Imidazoles/chemical synthesis , Imidazoles/pharmacology , Pyrroles/pharmacology , Animals , Asthma/drug therapy , Asthma/enzymology , Benzamides/chemistry , Benzamides/toxicity , Cytochrome P-450 Enzyme Inhibitors , Disease Models, Animal , Dose-Response Relationship, Drug , Drug Administration Schedule , Drug Design , Drug Evaluation, Preclinical , Enzyme Inhibitors/pharmacokinetics , Enzyme Inhibitors/toxicity , Humans , Imidazoles/pharmacokinetics , Imidazoles/toxicity , Lung/pathology , Lung/physiopathology , Mice , Molecular Structure , Molecular Targeted Therapy , No-Observed-Adverse-Effect Level , Pyrroles/chemistry , Pyrroles/toxicity , Receptors, Opioid, delta/metabolism , S-Nitrosoglutathione/metabolism , Structure-Activity RelationshipABSTRACT
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, cardiovascular, and gastrointestinal systems. The pyrrole based N6022 was recently identified as a potent, selective, reversible, and efficacious GSNOR inhibitor which is currently undergoing clinical development. We describe here the synthesis and structure-activity relationships (SAR) of novel pyrrole based analogues of N6022 focusing on scaffold modification and propionic acid replacement. We identified equally potent and novel GSNOR inhibitors having pyrrole regioisomers as scaffolds using a structure based approach.
Subject(s)
Aldehyde Oxidoreductases/antagonists & inhibitors , Benzamides/chemistry , Benzamides/pharmacology , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Propionates/chemistry , Propionates/pharmacology , Pyrroles/chemistry , Pyrroles/pharmacology , Benzamides/chemical synthesis , Enzyme Activation/drug effects , Enzyme Inhibitors/chemical synthesis , Inhibitory Concentration 50 , Molecular Structure , Propionates/chemical synthesis , Pyrroles/chemical synthesis , Stereoisomerism , Structure-Activity RelationshipABSTRACT
S-Nitrosoglutathione reductase (GSNOR) regulates S-nitrosothiols (SNOs) and nitric oxide (NO) in vivo through catabolism of S-nitrosoglutathione (GSNO). GSNOR and the anti-inflammatory and smooth muscle relaxant activities of SNOs, GSNO, and NO play significant roles in pulmonary, cardiovascular, and gastrointestinal function. In GSNOR knockout mice, basal airway tone is reduced and the response to challenge with bronchoconstrictors or airway allergens is attenuated. Consequently, GSNOR has emerged as an attractive therapeutic target for several clinically important human diseases. As such, small molecule inhibitors of GSNOR were developed. These GSNOR inhibitors were potent, selective, and efficacious in animal models of inflammatory disease characterized by reduced levels of GSNO and bioavailable NO. N6022, a potent and reversible GSNOR inhibitor, reduced bronchoconstriction and pulmonary inflammation in a mouse model of asthma and demonstrated an acceptable safety profile. N6022 is currently in clinical development as a potential agent for the treatment of acute asthma.
