Structure-activity relationship of pyrrole based S-nitrosoglutathione reductase inhibitors: carboxamide modification.
Xicheng Sun, Jian Qiu, Sarah A Strong, Louis S Green, Jan W F Wasley, Joan P Blonder, Dorothy B Colagiovanni, Adam M Stout, Sarah C Mutka, Jane P Richards, Gary J Rosenthal
Index: Bioorg. Med. Chem. Lett. 22(6) , 2338-42, (2012)
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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.Copyright © 2012 Elsevier Ltd. All rights reserved.
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