A nonclinical safety and pharmacokinetic evaluation of N6022: A first-in-class S-nitrosoglutathione reductase inhibitor for the treatment of asthma

• Published in: Regulatory toxicology and pharmacology Vol. 62; no. 1; pp. 115 - 124
• Main Authors: Colagiovanni, Dorothy B., Drolet, Daniel W., Langlois-Forget, Emilie, Piché, Marie-Pier, Looker, Doug, Rosenthal, Gary J.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Inc 01-02-2012
• Subjects: ADH3; Alanine Transaminase - blood; Aldehyde Oxidoreductases - antagonists & inhibitors; Alkaline Phosphatase - blood; Animals; Aspartate Aminotransferases - blood; Asthma - drug therapy; Benzamides - blood; Benzamides - pharmacokinetics; Benzamides - toxicity; Benzamides - urine; Bile - chemistry; Cell Line, Tumor; Cell Survival - drug effects; Class 3 alcohol dehydrogenase; Drug Evaluation, Preclinical; Enzyme Inhibitors - blood; Enzyme Inhibitors - pharmacokinetics; Enzyme Inhibitors - toxicity; Enzyme Inhibitors - urine; Feces - chemistry; Female; Glutathione - metabolism; GSNO; GSNO reductase; Liver - drug effects; Liver - metabolism; Liver - pathology; Lung - drug effects; Lung - pathology; Male; N6022; Pyrroles - blood; Pyrroles - pharmacokinetics; Pyrroles - toxicity; Pyrroles - urine; Rats; Rats, Sprague-Dawley; S-nitrosoglutathione; Safety evaluation; ADH3; GSNO reductase; Safety evaluation; S-nitrosoglutathione; GSNO; Class 3 alcohol dehydrogenase; N6022
• ISSN: 0273-2300; 1096-0295
• DOI: 10.1016/j.yrtph.2011.12.012

► Two weeks of daily N6022 via IV administration was well tolerated. ► High doses of N6022 caused possible liver toxicity related to redox status. ► Inhibiting GSNOR does not cause systemic toxicity.
S-nitrosoglutathione reductase is the primary enzyme responsible for the metabolism of S-nitrosoglutathione (GSNO), the body’s main source of bioavailable nitric oxide. Through its catabolic activity, GSNO reductase (GSNOR) plays a central role in regulating endogenous S-nitrosothiol levels and protein S-nitrosation-based signaling. By inhibiting GSNOR, we aim to increase pulmonary GSNO and induce bronchodilation while reducing inflammation in lung diseases such as asthma. To support the clinical development of N6022, a first-in-class GSNOR inhibitor, a 14-day toxicology study was conducted. Sprague–Dawley rats were given 2, 10 or 50mg/kg/dayN6022 via IV administration. N6022 was well tolerated at all doses and no biologically significant adverse findings were noted in the study up to 10mg/kg/day. N6022-related study findings were limited to the high dose group. One male rat had mild hepatocellular necrosis with accompanying increases in ALT and AST and several male animals had histological lung assessments with a slight increase in foreign body granulomas. Systemic exposure was greater in males than females and saturation of plasma clearance was observed in both sexes in the high dose group. Liver was identified as the major organ of elimination. Mechanistic studies showed dose-dependent effects on the integrity of a rat hepatoma cell line.