title: Structure-activity relationships of pyrrole based S-nitrosoglutathione reductase inhibitors: pyrrole regioisomers and propionic acid replacement.
abstract: 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, cardiovascular, and gastrointestinal systems. The pyrrole based N6022 was recently identified as a potent, selective, reversible, and efficacious GSNOR inhibitor which is currently undergoing clinical development. We describe here the synthesis and structure-activity relationships (SAR) of novel pyrrole based analogues of N6022 focusing on scaffold modification and propionic acid replacement. We identified equally potent and novel GSNOR inhibitors having pyrrole regioisomers as scaffolds using a structure based approach.
authors.affiliation: N30 Pharmaceuticals LLC, 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: Dorothy B
authors.initials: DB
authors.lastname: Colagiovanni
authors.forename: Sarah C
authors.initials: SC
authors.lastname: Mutka
authors.forename: Joan P
authors.initials: JP
authors.lastname: Blonder
authors.forename: Adam M
authors.initials: AM
authors.lastname: Stout
authors.forename: Jane P
authors.initials: JP
authors.lastname: Richards
authors.forename: Lawrence
authors.initials: L
authors.lastname: Chun
authors.forename: Gary J
authors.initials: GJ
authors.lastname: Rosenthal
mesh_terms: D000445:Aldehyde Oxidoreductases / Q000037:antagonists & inhibitors*; D001549:Benzamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D011422:Propionates / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D011758:Pyrroles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D001549:Benzamides; D004791:Enzyme Inhibitors; C571360:N6022; D011422:Propionates; D011758:Pyrroles; D000445:Aldehyde Oxidoreductases; C087006:formaldehyde dehydrogenase, glutathione-independent; C029658:propionic acid