DOI: 10.1002/cmdc.200600245 Inhibition of VAP1: Quickly Gaining Ground as an Anti-Inflammatory Therapy Francesc Yraola, [a, b] Fernando Albericio, [b] and Miriam Royo* [a] Research on VAP1/SSAO (vascular adhe- sion protein-1/semicarbazide-sensitive amine oxidase) has greatly intensified since Koskinen et al. published the first evidence that this protein is required for leukocyte rolling and transmigration through the endothelium (Figure 1). [1–3] This was the first report of VAP1-mediat- ed PMN (polymorphonuclear leukocyte) extravasion. Using an acute inflammation model, the authors evaluated BBT-2027, a small-molecule inhibitor of SSAO based on a hydrazine derivative devel- oped by BioTie Therapies Corporation. As VAP1 is one of the few proteins that shows SSAO activity in humans, it has quickly become a new target for anti-in- flammatory therapy. VAP1 is an ectoen- zyme that belongs to the family of semi- carbazide-sensitive copper-containing amine oxidases (EC 1.4.3.6) that converts primary amines to aldehydes via oxida- tive deamination with the concomitant production of H 2 O 2 and ammonia (Figure 1) . [4,5] Since the results published in 2004 with BBT-2027, BioTie has developed other alkylhydrazino derivatives, which have been rapidly moved to an early preclinical phase. At the beginning of 2005, BioTie and Roche Pharmaceuticals started a collaboration on the develop- ment of these small-molecule VAP1 in- hibitors. [a] F. Yraola, Dr. M. Royo Combinatorial Chemistry Unit Barcelona Science Park Josep Samitier 1–5, Barcelona (Spain) Fax: (+ 34)934-037-122 E-mail: mroyo@pcb.ub.es [b] F. Yraola, Prof. F. Albericio Institute for Research in Biomedicine Barcelona Science Park Josep Samitier 1–5, Barcelona (Spain) Figure 1. Schematic of the action of VAP1 during leukocyte–endothelial cell interaction, adapted by permission from Macmillan Publishers Ltd., copyright 2005, Nat. Rev. Immunol. 2005, 5, 760 (Ref. [1]). 1) While VAP1, bearing a topaquinone (TPQ, a modified Tyr) residue, is present in the endothelial cell, the leu- kocyte expresses a VAP1 ligand/substrate; 2) VAP1 binds to the leukocyte epitope. 3) A Schiff base is formed between the ligand/substrate of the leukocyte and TPQ of the active site of VAP1. 4) The amino group present in the leukocyte is oxidized with reestablishment of the TPQ residue and concomitant forma- tion of signaling side products (NH 3 and H 2 O 2 ). 3’) Alternatively, the process could be inhibited by small molecules that react with TPQ, resulting in selective blockage of leukocyte internalization. ChemMedChem 0000,00,1–3 # 2006 Wiley-VCH Verlag GmbH&Co. KGaA, Weinheim &1& These are not the final page numbers! ÞÞ