PXS-4681A, a potent and selective mechanism-based inhibitor of SSAO/VAP-1 with anti-inflammatory effects in vivo.
Semicarbazide-sensitive amine oxidase (SSAO), also known as vascular adhesion protein-1 (VAP-1), is a member of the copper-dependent 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, long-lasting inhibition of the enzyme after a single low dose in vivo. PXS-4681A irreversibly inhibits the enzyme with an apparent Ki of 37 nM and a kinact of 0.26 min(-1) 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-α, and interleukin-6 levels. These results demonstrate the drug-like properties of PXS-4681A and its potential use in the treatment of inflammation.
Pharmaxis Ltd., Frenchs Forest, New South Wales, Australia.
Jonathan S
JS
Foot
Tin T
TT
Yow
Heidi
H
Schilter
Alberto
A
Buson
Mandar
M
Deodhar
Alison D
AD
Findlay
Lily
L
Guo
Ian A
IA
McDonald
Craig I
CI
Turner
Wenbin
W
Zhou
Wolfgang
W
Jarolimek
D000273:Adipose Tissue / Q000187:drug effects / Q000201:enzymology; D000498:Allyl Compounds / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D006631:Amine Oxidase (Copper-Containing) / Q000037:antagonists & inhibitors*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D015815:Cell Adhesion Molecules / Q000037:antagonists & inhibitors*; D003872:Dermatitis / Q000188:drug therapy / Q000201:enzymology / Q000276:immunology; D004195:Disease Models, Animal; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D008861:Microsomes / Q000187:drug effects / Q000201:enzymology; D008954:Models, Biological; D015394:Molecular Structure; D011014:Pneumonia / Q000188:drug therapy / Q000201:enzymology / Q000276:immunology; D011817:Rabbits; D051381:Rats; D054852:Small Molecule Libraries / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D013045:Species Specificity; D013449:Sulfonamides / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D000096926:Benzenesulfonamides
D000498:Allyl Compounds; D006631:Amine Oxidase (Copper-Containing); D000893:Anti-Inflammatory Agents; D015815:Cell Adhesion Molecules; D004791:Enzyme Inhibitors; D054852:Small Molecule Libraries; D013449:Sulfonamides; C585144:4-(2-(aminomethyl)-3-fluoroallyloxy)benzenesulfonamide; D000096926:Benzenesulfonamides; C076668:AOC3 protein, human