Targeting vascular adhesion protein-1 and myeloperoxidase with a dual inhibitor SNT-8370 in preclinical models of inflammatory disease

Elias Glaros, Jonathan Foot, Ben Rayner, Heidi Schilter, Yunjia Zhang, Martina Paumann-Page, Mauro M. Teixeira, Wolfgang Jarolimek () and Shane R. Thomas ()
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Elias Glaros: University of New South Wales
Jonathan Foot: Syntara Ltd
Ben Rayner: The University of Sydney
Heidi Schilter: Syntara Ltd
Yunjia Zhang: University of New South Wales
Martina Paumann-Page: University of Otago
Mauro M. Teixeira: Universidade Federal de Minas Gerais
Wolfgang Jarolimek: Syntara Ltd
Shane R. Thomas: University of New South Wales

Nature Communications, 2025, vol. 16, issue 1, 1-18

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-58454-6

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