PXS-4681A, a Potent and Selective Mechanism-Based Inhibitor of SSAO/VAP-1 with Anti-Inflammatory Effects In Vivo

Abstract

Semicarbazide-sensitive amine oxidase (SSAO), also known as vascular adhesion protein-1 (VAP-1), is a member of the copperdependent amine oxidase family that is associated with various forms of inflammation and fibrosis. To investigate the therapeutic potential of SSAO/VAP-1 inhibition, potent and selective inhibitors with drug-like properties are required. PXS-4681A [(Z)-4-(2-(aminomethyl)-3-fluoroallyloxy)benzenesulfonamide hydrochloride] is a mechanism-based inhibitor of enzyme function with a pharmacokinetic and pharmacodynamic profile that ensures complete, longlasting inhibition of the enzyme after a single low dose in vivo.PXS-4681A irreversibly inhibits the enzyme with an apparent K i of 37 nM and a k inact of 0.26 min 21 with no observed turnover in vitro. It is highly selective for SSAO/VAP-1 when profiled against related amine oxidases, ion channels, and seven-transmembrane domain receptors, and is superior to previously reported inhibitors. In mouse models of lung inflammation and localized inflammation, dosing of this molecule at 2 mg/kg attenuates neutrophil migration, tumor necrosis factor-a, and interleukin-6 levels. These results demonstrate the drug-like properties of PXS-4681A and its potential use in the treatment of inflammation.

Analgesic and Anti-Inflammatory Effects of the Novel Semicarbazide-Sensitive Amine-Oxidase Inhibitor SzV-1287 in Chronic Arthritis Models of the Mouse

“…The latter effect is supported by some publications showing SSAO activity in the mouse brain both in the endothelial cells of microvessels and neurons4647. Despite the fact that a range of anti-inflammatory effects LJP-1207 have been shown in several inflammation models including colitis, multiple sclerosis, LPS-induced endotoxemia and stroke4849, it is not a suitable compound for drug development, because as a hydrazine derivative it is potentially toxic upon repeated exposure2150.…”

“…Furthermore, several compounds possess unfavourable physicochemical properties, such as poor solubility, and they contain certain functional groups (e.g. hydrazine), posing potential toxicity (LJP-1207 and BTT-2052)21.…”

Pre-clinical evaluation of small molecule LOXL2 inhibitors in breast cancer

“…Derivation of an alternative (haloallylamine-based) inhibitor scaffold has now led to the development of new compounds [13, 14] with different selectivity profiles to facilitate such investigations. These compounds are mechanism-based inhibitors with drug-like properties.…”

The inhibitor of semicarbazide‐sensitive amine oxidase, PXS‐4728A, ameliorates key features of chronic obstructive pulmonary disease in a mouse model

“…We and others have previously demonstrated that macrophages play important roles in CS‐induced pathogenesis (Duan et al, ; Lenzo et al, ; Beckett et al, ), and their depletion prevented the development of experimental COPD (Beckett et al, ). While its effects on neutrophils has been well documented (Yu et al, ; Kiss et al, ; Foot et al, ), there has been no previously reported direct effect of alterations in SSAO activity on macrophages. The acute reduction in inflammatory cells was accompanied by significant decreases in the protein levels of the pro‐inflammatory cytokine TNFα.…”

“…The PXS‐4728A doses used were initially based on previous studies which defined the pharmacodynamic and pharmacokinetic properties of the inhibitor. In particular, its selectivity in targeting SSAO and its bioavailability and its lack of off‐target effects (Foot et al, ; Schilter et al, ). Oral treatment also inhibited systemic SSAO activity, as determined in inguinal fat after acute CS‐exposure.…”