Benefit of inhibiting SSAO in relapsing experimental autoimmune encephalomyelitis.
We have developed several series of potent and selective small molecule inhibitors of SSAO (AOC3/VAP-1) that also block trafficking of leukocytes to sites of inflammation. Blocking of SSAO-mediated leukocyte adhesion has recently been shown efficacious in several models of inflammatory diseases. We have examined the potential of SSAO inhibitors in neurological diseases, having previously demonstrated the efficacy of SSAO inhibition in a rat model of stroke. Here we show the effect of the small molecule SSAO inhibitor LJP 1207 (IC(50) human SSAO 17 nM; ratio IC(50) SSAO:MAO >5000), on relapsing-remitting experimental autoimmune encephalomyelitis (EAE), a mouse model that shares many characteristics with human multiple sclerosis. Clinical efficacy was observed when dosing with LJP 1207 was initiated either at the peak of initial flare or during remission. These data demonstrate the potential clinical benefit of small molecule anti-SSAO therapy in this model.
O'Rourke
A M
AM
La Jolla Pharmaceutical Company, San Diego, CA 92121, USA.
Wang
E Y
EY
Salter-Cid
L
L
Huang
L
L
Miller
A
A
Podar
E
E
Gao
H F
HF
Jones
D S
DS
Linnik
M D
MD
D006631:Amine Oxidase (Copper-Containing) / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D000818:Animals; D002448:Cell Adhesion / Q000187:drug effects / Q000502:physiology; D015815:Cell Adhesion Molecules / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D002634:Chemotaxis, Leukocyte / Q000187:drug effects / Q000276:immunology; D018450:Disease Progression; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy* / Q000201:enzymology* / Q000503:physiopathology; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D006834:Hydrazines / Q000494:pharmacology* / Q000627:therapeutic use; D007165:Immunosuppression Therapy / Q000379:methods; D051379:Mice; D009103:Multiple Sclerosis / Q000188:drug therapy / Q000201:enzymology / Q000503:physiopathology; D055502:Secondary Prevention; D016896:Treatment Outcome
D015815:Cell Adhesion Molecules; D004791:Enzyme Inhibitors; D006834:Hydrazines; C506836:N'-(2-phenylallyl)hydrazine; D006631:Amine Oxidase (Copper-Containing); C492678:semicarbazide-sensitive amine oxidase-vascular adhesion protein-1, mouse