br S Nitrosoglutathione reductase GSNOR also identified as g

S-Nitrosoglutathione reductase (GSNOR) also identified as glutathione-dependent formaldehyde dehydrogenase (FDH), is a zinc-dependent dehydrogenase. It is a member of the alcohol dehydrogenase (ADH) family and is called class III alcohol dehydrogenase that regulates the levels of S-nitrosothiols (SNOs) through catabolism of S-nitrosoglutathione (GSNO). The importance of GSNOR in controlling the levels of both intracellular GSNO and nitrosated proteins was established in knockout models of yeast and the nomenclature “GSNO reductase” was introduced to reflect this important physiological role. GSNOR enzyme that catalyzes the reduction of S-nitrosoglutathione has been recognized as a potential therapeutic target and it products GSNO and SNOs are implicated in many diseases including respiratory, cardiovascular (pulmonary hypertension, thrombosis and altered platelet function), gastrointestinal systems (inflammatory bowel diseases), cerebral ischemia and compromised host defense. GSNOR is a highly conserved enzyme and can be found in both prokaryotic and eukaryotic organisms. Although GSNOR is expressed in all tissues, its activity levels are highest in the liver followed by kidney, heart, lung, spleen and thymus. Cellular GSNO is one of the major source of biologically stable nitric oxide (NO), thus forms adducts with cysteine containing peptides and proteins. Therefore, inhibition of GSNOR prevents GSNO metabolism and allows accumulation of GSNO, which leads to protein S-nitrosylation. It is also thought to influence the levels of NO and nitrite (NO−) that form via reactions of GSNO with glutathione (GSH) or various reactive oxygen or nitrogen species. The role of GSNOR in NO metabolism is further established by studies in GSNOR knockout mice., Moreover, an increase of GSNO in an OVA-sensitized and OVA-challenged mice ameliorated airway hyper reactivity (AHR). Overall, these studies suggest that a therapeutic approach in which airway GSNO levels are increased by treatment with GSNOR inhibitors could provide a novel therapeutic approach for reducing allergic inflammation, AHR in asthma, COPD and other related lung diseases. The therapeutic utility of GSNOR inhibitors were well established in animal models of tandospirone and COPD, which provided a rational for inhibiting GSNOR as a drug target for respiratory indication. The campaign to identify a potent and selective GSNOR inhibitor attained a significant milestone with the discovery of N6022 () and N91115 () ()., , , , N6022 is a potent and selective GSNOR inhibitor (human GSNOR IC: 20 nM) and has >1000-fold selective over other human ADH enzymes. N6022 did not inhibit hERG channel and was negative in Ames, but it has poor oral bioavailability (%F: <10%) and significant CYP liability., N6022 has completed Ph-I clinical trial as agent to treat acute asthma. N91115 () is also a potent GSNOR inhibitor (GSNOR hIC: 16 nM) which has good oral bioavailability and has completed Ph-II clinical trials recently for cystic fibrosis. Likewise, another GSNOR inhibitor is also disclosed by Nivalis Pharma having human GSNOR potency of 37 nM IC, respectively (). As part of our on-going drug discovery program in the respiratory indication, we identified N91115 () as a potential starting point to design novel GSNOR inhibitor. Applying scaffold hopping strategy led to novel GSNOR inhibitor which was expected to retain GSNOR potency similar to as exemplified in . The bioisosteric replacement of the carboxylic acid in compound with tetrazole led to compound which was projected to offer enhanced GSNOR potency and favorable pharmacokinetic properties. In this letter, we describe the synthesis and pharmacological activity of 4′-(1-imidazol-1-yl)-[1,1′-biphenyl]-4-carboxylic acid derivatives and 5-(4′-(1-imidazol-1-yl)-[1,1′-biphenyl]-4-yl)-1-tetrazole derivatives as depicted in , , and , , . Commercially available 4′-bromo-[1,1′-biphenyl]-4-carbonitrile () was reacted with imidazole in the presence of CuI to afford compound . The nitrile in compound was hydrolyzed independently to amide and carboxylic acid as shown in . Further, the biaryl nitrile was converted to tetrazole using NaN in DMF at 100 °C. Next, the reaction of with hydroxylamine hydrochloride to afford biphenyl carboximidamide , followed by CDI reaction in THF at 70 °C afforded 1,2,4-oxadiazol-5(2)-one derivative in 55% yield. Further, compounds and were prepared by reacting commercially available 1,1′-biphenyl-4,4′-dicarbonitrile with one equivalent of NaN and as well as excess NaN in the presence of EtNHCl in DMF to afford in 30% and 70% yield (). Compounds and shown in were prepared as described in . Commercially available 4-amino-3-chlorobenzonitrile was subjected to Sandmeyer reaction to afford iodo compound , followed by Suzuki coupling with 4-bromophenylboronic acid and 4-aminophenylboronic acid independently to afford compounds 1 and , respectively. Compound was reacted with 1,2,4-triazole in the presence of CuI and KCO to provide compound , followed by tetrazole formation using NaN to give compound in 60% yield. Similarly, -tetrazole compound was prepared by reaction of with NaN and trimethyl orthoformate in acetic acid, followed by tetrazole formation afforded - and C-linked tetrazole in 55% yield.