title: Discovery of potent and novel S-nitrosoglutathione reductase inhibitors devoid of cytochrome P450 activities.
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.
authors.affiliation: N30 Pharmaceuticals LLC, 3122 Sterling Circle, Suite 200, Boulder, CO 80301, USA. xicheng.sun@n30pharma.com
authors.forename: Xicheng
authors.initials: X
authors.lastname: Sun
authors.forename: Jian
authors.initials: J
authors.lastname: Qiu
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Strong
authors.forename: Louis S
authors.initials: LS
authors.lastname: Green
authors.forename: Jan W F
authors.initials: JW
authors.lastname: Wasley
authors.forename: Joan P
authors.initials: JP
authors.lastname: Blonder
authors.forename: Dorothy B
authors.initials: DB
authors.lastname: Colagiovanni
authors.forename: Sarah C
authors.initials: SC
authors.lastname: Mutka
authors.forename: Adam M
authors.initials: AM
authors.lastname: Stout
authors.forename: Jane P
authors.initials: JP
authors.lastname: Richards
authors.forename: Gary J
authors.initials: GJ
authors.lastname: Rosenthal
mesh_terms: D000445:Aldehyde Oxidoreductases / Q000037:antagonists & inhibitors*; D000818:Animals; D001249:Asthma / Q000188:drug therapy / Q000201:enzymology; D001549:Benzamides / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D008168:Lung / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D015394:Molecular Structure; D058990:Molecular Targeted Therapy; D019055:No-Observed-Adverse-Effect Level; D011758:Pyrroles / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D017465:Receptors, Opioid, delta / Q000378:metabolism; D026422:S-Nitrosoglutathione / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D001549:Benzamides; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D007093:Imidazoles; C571360:N6022; D011758:Pyrroles; D017465:Receptors, Opioid, delta; D026422:S-Nitrosoglutathione; D003577:Cytochrome P-450 Enzyme System; D000445:Aldehyde Oxidoreductases; C087006:formaldehyde dehydrogenase, glutathione-independent