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

Xicheng Sun; Jian Qiu; Sarah A Strong; Louis S Green; Jan W F Wasley; Joan P Blonder; Dorothy B Colagiovanni; Sarah C Mutka; Adam M Stout; Jane P Richards; Gary J Rosenthal

doi:10.1016/j.bmcl.2011.07.103

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

Bioorg Med Chem Lett. 2011 Oct 1;21(19):5849-53. doi: 10.1016/j.bmcl.2011.07.103. Epub 2011 Aug 3.

Authors

Xicheng Sun¹, Jian Qiu, Sarah A Strong, Louis S Green, Jan W F Wasley, Joan P Blonder, Dorothy B Colagiovanni, Sarah C Mutka, Adam M Stout, Jane P Richards, Gary J Rosenthal

Affiliation

¹ N30 Pharmaceuticals LLC, 3122 Sterling Circle, Suite 200, Boulder, CO 80301, USA. xicheng.sun@n30pharma.com

PMID: 21855338
DOI: 10.1016/j.bmcl.2011.07.103

Abstract

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.

MeSH terms

Aldehyde Oxidoreductases / antagonists & inhibitors*
Animals
Asthma / drug therapy
Asthma / enzymology
Benzamides / chemistry
Benzamides / pharmacology*
Benzamides / toxicity
Cytochrome P-450 Enzyme Inhibitors
Cytochrome P-450 Enzyme System / metabolism*
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
Humans
Imidazoles / chemical synthesis*
Imidazoles / pharmacokinetics
Imidazoles / pharmacology*
Imidazoles / toxicity
Lung / pathology
Lung / physiopathology
Mice
Molecular Structure
Molecular Targeted Therapy
No-Observed-Adverse-Effect Level
Pyrroles / chemistry
Pyrroles / pharmacology*
Pyrroles / toxicity
Receptors, Opioid, delta / metabolism
S-Nitrosoglutathione / metabolism
Structure-Activity Relationship

Substances

Benzamides
Cytochrome P-450 Enzyme Inhibitors
Enzyme Inhibitors
Imidazoles
N6022
Pyrroles
Receptors, Opioid, delta
S-Nitrosoglutathione
Cytochrome P-450 Enzyme System
Aldehyde Oxidoreductases
formaldehyde dehydrogenase, glutathione-independent