Anti-inflammatory effects of LJP 1586 [Z-3-fluoro-2-(4-methoxybenzyl)allylamine hydrochloride], an amine-based inhibitor of semicarbazide-sensitive amine oxidase activity.
Semicarbazide-sensitive amine oxidase (SSAO, amine oxidase, copper-containing 3, and vascular adhesion protein-1) is a copper-containing enzyme that catalyzes the oxidative deamination of primary amines to an aldehyde, ammonia, and hydrogen peroxide. SSAO is also involved in leukocyte migration to sites of inflammation, and the enzymatic activity of SSAO is essential to this role. Thus, inhibition of SSAO enzyme activity represents a target for the development of small molecule anti-inflammatory compounds. Here, we have characterized the novel SSAO inhibitor, Z-3-fluoro-2-(4-methoxybenzyl)allylamine hydrochloride (LJP 1586), and assessed its anti-inflammatory activity. LJP 1586 is a potent inhibitor of rodent and human SSAO activity, with IC(50) values between 4 and 43 nM. The selectivity of LJP 1586 was confirmed with a broad panel of receptors and enzymes that included the monoamine oxidases A and B. Oral administration of LJP 1586 resulted in complete inhibition of rat lung SSAO, with an ED(50) between 0.1 and 1 mg/kg, and a pharmacodynamic half-life of greater than 24 h. In a mouse model of inflammatory leukocyte trafficking oral dosing with LJP 1586 resulted in significant dose-dependent inhibition of neutrophil accumulation, with an effect comparable to that of anti-leukocyte function-associated antigen-1 antibody. In a rat model of LPS-induced lung inflammation, administration of 10 mg/kg LJP 1586 resulted in a 55% significant reduction in transmigrated cells recovered by bronchoalveolar lavage. The results demonstrate that a selective, orally active small molecule inhibitor of SSAO is an effective anti-inflammatory compound in vivo and provide further support for SSAO as a therapeutic anti-inflammatory target.
O'Rourke
Anne M
AM
La Jolla Pharmaceutical Company, 6455 Nancy Ridge Drive, San Diego, CA 92121, USA. anne.orourke@ljpc.com
Wang
Eric Y
EY
Miller
Andrew
A
Podar
Erika M
EM
Scheyhing
Kelly
K
Huang
Li
L
Kessler
Christina
C
Gao
Hongfeng
H
Ton-Nu
Huong-Thu
HT
Macdonald
Mary T
MT
Jones
David S
DS
Linnik
Matthew D
MD
D000499:Allylamine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D006631:Amine Oxidase (Copper-Containing) / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000588:Amines / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D006801:Humans; D007249:Inflammation / Q000188:drug therapy / Q000201:enzymology; D008168:Lung / Q000187:drug effects / Q000201:enzymology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D051381:Rats; D017207:Rats, Sprague-Dawley
C526615:3-fluoro-2-(4-methoxybenzyl)allylamine; D000588:Amines; D000894:Anti-Inflammatory Agents, Non-Steroidal; D004791:Enzyme Inhibitors; D000499:Allylamine; D006631:Amine Oxidase (Copper-Containing)