POTENT AND SELECTIVE SEMICARBAZIDE-SENSITIVE AMINE OXIDASE (SSAO) INHIBITORS WITH ANTI-INFLAMMATORY ACTIVITIES

Eric Y. Wang*, Hongfeng Gao, Luisa Salter-Cid, Jun Zhang, Li Huang, Erika Podar, Andrew Miller, and Matthew D Linnik

Abstract

In an attempt to examine the effect of inhibition of semicarbazide-sensitive amine oxidase (SSAO; EC 1.4.3.6, also known as VAP-1) as a novel anti-inflammatory target, the structure/mechanism based design and synthesis of a series of novel hydrazino-containing small molecules are described. The in vitro biological results show that compounds 4a,c are highly potent SSAO inhibitors with notable selectivity toward SSAO over monoamine oxidases A and B (MAO-A and MAO-B). SAR studies based on compound 4c were performed, and the results are discussed. The most potent and selective compound, 4a (IC(50) = 2 nM), is an orally active, competitive, and apparently irreversible inhibitor of SSAO that is effective at reducing disease incidence and severity in an in vivo animal disease model of multiple sclerosis.

Published in
Journal of Medical Chemistry
April 2006
Volume 46, No. 7 pp 2166-217