title: Structure-activity relationship of pyrrole based S-nitrosoglutathione reductase inhibitors: carboxamide modification.
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.
authors.affiliation: N30 Pharmaceuticals LLC, 3122 Sterling Circle, 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: Adam M
authors.initials: AM
authors.lastname: Stout
authors.forename: Sarah C
authors.initials: SC
authors.lastname: Mutka
authors.forename: Jane P
authors.initials: JP
authors.lastname: Richards
authors.forename: Gary J
authors.initials: GJ
authors.lastname: Rosenthal
mesh_terms: D000208:Acute Disease; D000445:Aldehyde Oxidoreductases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D018927:Anti-Asthmatic Agents / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000627:therapeutic use; D001249:Asthma / Q000139:chemically induced / Q000188:drug therapy* / Q000201:enzymology; D001549:Benzamides / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000627:therapeutic use; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000627:therapeutic use; D006801:Humans; D008297:Male; D051379:Mice; D010047:Ovalbumin; D011758:Pyrroles / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000627:therapeutic use; D026422:S-Nitrosoglutathione / Q000378:metabolism; D026403:S-Nitrosothiols / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D018927:Anti-Asthmatic Agents; D001549:Benzamides; D004791:Enzyme Inhibitors; C571360:N6022; D011758:Pyrroles; D026403:S-Nitrosothiols; D026422:S-Nitrosoglutathione; D010047:Ovalbumin; D000445:Aldehyde Oxidoreductases; C087006:formaldehyde dehydrogenase, glutathione-independent