TY - JOUR
T1 - Novel pyridazinone inhibitors for vascular adhesion protein-1 (VAP-1)
T2 - Old target-new inhibition mode
AU - Bligt-Lindén, Eva
AU - Pihlavisto, Marjo
AU - Szatmári, István
AU - Otwinowski, Zbyszek
AU - Smith, David J.
AU - Lázár, László
AU - Fülöp, Ferenc
AU - Salminen, Tiina A.
N1 - Copyright:
Copyright 2014 Elsevier B.V., All rights reserved.
PY - 2013/12/27
Y1 - 2013/12/27
N2 - 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.
AB - 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.
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U2 - 10.1021/jm401372d
DO - 10.1021/jm401372d
M3 - Article
C2 - 24304424
AN - SCOPUS:84891316808
SN - 0022-2623
VL - 56
SP - 9837
EP - 9848
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 24
ER -