The discovery and development of selective 3-fluoro-4-aryloxyallylamine inhibitors of the amine oxidase activity of semicarbazide-sensitive amine oxidase/vascular adhesion protein-1 (SSAO/VAP-1) Jonathan S. Foot a,⇑ , Mandar Deodhar a , Craig I. Turner a , Ping Yin a , Ellen M. van Dam a , Diego G. Silva a , Aldo Olivieri b , Andrew Holt b , Ian A. McDonald a a Pharmaxis Ltd., 20 Rodborough Road, Frenchs Forest, NSW 2086, Australia b Department of Pharmacology, University of Alberta, Edmonton, AB, Canada T6G 2H7 article info Article history: Received 7 March 2012 Revised 18 April 2012 Accepted 23 April 2012 Available online 30 April 2012 Keywords: SSAO VAP-1 Allylamines Amine oxidase abstract A new class of 3-fluoroallyl amine-based SSAO/VAP-1 inhibitors is reported. These compounds have excellent selectivity over diamine oxidase, MAO-A and MAO-B. Synthesis and SAR studies leading to com- pound 28 (PXS-4159A) are reported. The pharmacokinetic profile of 28 in the rat, together with activity in a murine model of lung inflammation are also disclosed. Ó 2012 Elsevier Ltd. All rights reserved. Semicarbazide-sensitive amine oxidase (AOC3, also known as vascular adhesion protein-1 [VAP-1], primary amine oxidase or plasma amine oxidase, EC 1.4.3.21) is a member of the copper- dependent family of amine oxidases (AOC). 1 SSAO/VAP-1 is a type 1 membrane-bound protein which has a distal adhesion domain and a catalytic amine oxidase site proximal to the membrane. Both sites have been shown to be critical for SSAO/VAP-1-mediated inhibition of leukocyte rolling, adhesion and transmigration in response to inflammatory stimuli. 2 SSAO/VAP-1 catalyzes the oxi- dation of primary amines to aldehydes with release of ammonia and hydrogen peroxide (Scheme 1) and is sensitive to carbonyl- reactive reagents (such as semicarbazide), but insensitive to selec- tive flavin-dependent MAO-A and MAO-B enzyme inhibitors like selegiline and clorgyline. In humans four AOC genes are known; three (AOC-1–3) trans- late into enzymatically active protein and one (AOC-4) into a trun- cated inactive form. 3 AOC-1 codes for a diamine oxidase (DAO) found in the kidney, gut and lung and is involved in the metabo- lism of endogenous histamine. AOC-2 encodes for retinal amine oxidase which is found almost exclusively in the eye. 4 AOC-3 encodes for the primary monoamine oxidase SSAO/VAP-1 and is found in adipocytes, smooth muscle cells and endothelial cells, and is highly expressed in the lung, aorta, liver and ileum. 5 Membrane bound SSAO/VAP-1 is proteolytically cleaved by a metalloprotease to release an active, soluble form of the protein. 6 Endogenous substrates for SSAO/VAP-1 include methylamine and aminoacetone. 7 The enzyme also oxidizes other substrates, such as benzylamine, which is often used as the substrate to assay enzymatic activity. There are considerable substrate and inhibitor differences amongst species so it can be challenging to design po- tent inhibitors of human SSAO/VAP-1 with similar inhibitory potency against the rodent and canine enzymes. 8 Different classes of SSAO/VAP-1 inhibitors have been reported in the literature and have been reviewed thoroughly elsewhere. 9 Inhibition of SSAO/VAP-1 has been shown to be efficacious in ro- dent models of eye inflammation, rheumatoid arthritis, carrageen air-pouch inflammation, liver fibrosis, and stroke, amongst other inflammatory models. 10 In addition, some inhibitors have proven efficacious in lung inflammatory responses. 10b For example, mofegiline (1) attenuates the LPS-induced lung inflammatory response in mice over expressing human SSAO/VAP-1. 11 Therefore selective SSAO/VAP-1 inhibitors have the potential to treat lung inflammation in humans, including neutrophil-driven processes, such as severe asthma. The focus of this research project is to develop inhibitors for this indication. Mofegiline (Fig. 1. 1), which progressed to Phase 2 clinical trials as an adjunct to L-dopa for the treatment of Parkinson’s disease, is a well known inhibitor of the amine oxidase activity of SSAO/VAP-1. 0960-894X/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.bmcl.2012.04.111 ⇑ Corresponding author. E-mail address: jonathan.foot@pharmaxis.com.au (J.S. Foot). Bioorganic & Medicinal Chemistry Letters 22 (2012) 3935–3940 Contents lists available at SciVerse ScienceDirect Bioorganic & Medicinal Chemistry Letters journal homepage: www.elsevier.com/locate/bmcl