Discovery of potent and novel S-nitrosoglutathione reductase inhibitors devoid of cytochrome P450 activities

• Published in: Bioorganic & medicinal chemistry letters Vol. 21; no. 19; pp. 5849 - 5853
• Main Authors: Sun, Xicheng, Qiu, Jian, Strong, Sarah A., Green, Louis S., Wasley, Jan W.F., Blonder, Joan P., Colagiovanni, Dorothy B., Mutka, Sarah C., Stout, Adam M., Richards, Jane P., Rosenthal, Gary J.
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 01-10-2011; Elsevier
• Subjects: alcohol dehydrogenase; Aldehyde Oxidoreductases - antagonists & inhibitors; Animals; asthma; Asthma - drug therapy; Asthma - enzymology; Benzamides - chemistry; Benzamides - pharmacology; Benzamides - toxicity; Biological and medical sciences; Bones, joints and connective tissue. Antiinflammatory agents; cytochrome P-450; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System - metabolism; Cytochrome P450; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Design; Drug Evaluation, Preclinical; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - pharmacokinetics; Enzyme Inhibitors - pharmacology; Enzyme Inhibitors - toxicity; gastrointestinal system; GSNO; GSNOR; GSNOR inhibitor; Humans; Imidazoles - chemical synthesis; Imidazoles - pharmacokinetics; Imidazoles - pharmacology; Imidazoles - toxicity; Lung - pathology; Lung - physiopathology; Medical sciences; metabolism; Mice; Molecular Structure; Molecular Targeted Therapy; N6022; Nitric oxide; No-Observed-Adverse-Effect Level; ovalbumin; pathogenesis; Pharmacology. Drug treatments; Pyrroles - chemistry; Pyrroles - pharmacology; Pyrroles - toxicity; Receptors, Opioid, delta - metabolism; S-Nitrosoglutathione - metabolism; Structure-Activity Relationship; structure-activity relationships; GSNOR inhibitor; NO; Nitric oxide; Cytochrome P450; SNOs; GSNOR; GSNO; N6022; Imidazole derivatives; Enzyme; Enzyme inhibitor; Selectivity; S-(hydroxymethyl)glutathione dehydrogenase; Biological activity; Thiophene derivatives; Carboxylic acid; Carboxamide; Benzamide derivatives; Oxidoreductases; Chemical synthesis
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2011.07.103

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.