Novel Pyridazinone Inhibitors for Vascular Adhesion Protein-1 (VAP-1): Old Target-New Inhibition Mode

A1 Journal article (refereed)


Internal Authors/Editors


Publication Details

List of Authors: Eva Bligt-Lindén, Marjo Pihlavisto, István Szatmári, Zbyszek Otwinowski, David J. Smith, László Lázár, Ferenc Fülöp, Tiina A. Salminen
Publisher: AMER CHEMICAL SOC
Publication year: 2013
Journal: Journal of Medicinal Chemistry
Journal acronym: J MED CHEM
Volume number: 56
Issue number: 24
Start page: 9837
End page: 9848
Number of pages: 12
ISSN: 0022-2623


Abstract

Vascular adhesion protein-1 (VAP-1) is a primary amine oxidase and a drug target for inflammatory and vascular diseases. Despite extensive attempts to develop potent, specific, and reversible inhibitors of its enzyme activity, the task has proven challenging. Here we report the synthesis, inhibitory activity, and molecular binding mode of novel pyridazinone inhibitors, which show specificity for VAP-1 over monoamine and diamine oxidases. The crystal structures of three inhibitor VAP-1 complexes show that these compounds bind reversibly into a unique binding site in the active site channel. Although they are good inhibitors of human VAP-1, they do not inhibit rodent VAP-1 well. To investigate this further, we used homology modeling and structural comparison to identify amino acid differences, which explain the species-specific binding properties. Our results prove the potency and specificity of these new inhibitors, and the detailed characterization of their binding mode is of importance for further development of VAP-1 inhibitors.

Last updated on 2019-22-08 at 06:52