The persistent influx of neutrophils into the lung and subsequent tissue damage are characteristics of COPD, cystic fibrosis and acute lung inflammation. VAP-1/SSAO is an endothelial bound adhesion molecule with amine oxidase activity that is reported to be involved in neutrophil egress from the microvasculature during inflammation. This study explored the role of VAP-1/SSAO in neutrophilic lung mediated diseases and examined the therapeutic potential of the selective inhibitor PXS-4728A. Mice treated with PXS-4728A underwent intra-vital microscopy visualization of the cremaster muscle upon CXCL1/KC stimulation. LPS inflammation, Klebsiella pneumoniae infection, cecal ligation and puncture as well as rhinovirus exacerbated asthma models were also assessed using PXS-4728A. Selective VAP-1/SSAO inhibition by PXS-4728A diminished leukocyte rolling and adherence induced by CXCL1/KC. Inhibition of VAP-1/SSAO also dampened the migration of neutrophils to the lungs in response to LPS, Klebsiella pneumoniae lung infection and CLP induced sepsis; whilst still allowing for normal neutrophil defense function, resulting in increased survival. The functional effects of this inhibition were demonstrated in the RV exacerbated asthma model, with a reduction in cellular infiltrate correlating with a reduction in airways hyperractivity. This study demonstrates that the endothelial cell ligand VAP-1/SSAO contributes to the migration of neutrophils during acute lung inflammation, pulmonary infection and airway hyperractivity. These results highlight the potential of inhibiting of VAP-1/SSAO enzymatic function, by PXS-4728A, as a novel therapeutic approach in lung diseases that are characterized by neutrophilic pattern of inflammation.

With certain substituent patterns, benzyl benzyl sulfone systems have been found to give unexpectedly high Z-stereoselectivity (up to E : Z = 1 : 16) in the Meyers variant of the Ramberg–Bäcklund reaction. A range of sulfones, bearing various aryl substituents, were explored to rationalize this unprecedented selectivity for Z-stilbene systems. This high level of double bond stereocontrol has also been utilized in the synthesis of integrastatin nucleus, the core of two highly bioactive anti-HIV compounds.

Inflammatory diseases are a major source of morbidity and mortality world-wide, the pathogenesis of which are characterised by the interplay of key pro-inflammatory and oxidative enzymes. Here, we report the development of a small molecule dual inhibitor targeting vascular adhesion protein-1 (VAP-1) and myeloperoxidase (MPO), two clinically relevant pro-inflammatory/oxidative enzymes that play complementary pathogenic roles in various inflammatory diseases. This agent, SNT-8370 [(E)-3-(3-((2-(aminomethyl)-3-fluoroallyl)oxy)benzyl)-2-thioxo-1,2,3,7-tetrahydro-6H-purin-6-one)], irreversibly inhibits VAP-1 and MPO activity with equivalent and enhanced nanomolar potency, respectively, when compared to benchmark clinical VAP-1 and MPO inhibitors. SNT-8370 is selective, exhibiting >100-1000-fold more potency for VAP-1 and MPO versus other mammalian (per)oxidases and shows no significant off-target activity in established preclinical screening panels. In vivo, SNT-8370 is metabolically stable, exhibits a favourable pharmacokinetic/pharmacodynamic profile without CNS penetration, and effectively inhibits VAP-1 and MPO activities. Moreover, compared to monotherapy, SNT-8370 more effectively inhibits leukocyte infiltration in mouse peritonitis, carrageenan air pouch, and lipopolysaccharide-induced lung injury models of acute inflammation. SNT-8370 is also protective in preclinical models of myocardial ischemia-reperfusion injury and unilateral-ureteral-obstruction-induced nephropathy. Collectively, our results support SNT-8370 as a first-in-class, mechanism-based dual inhibitor of VAP-1 and MPO, and as a promising therapeutic for the clinical treatment of inflammatory disorders.