Semicarbazide-Sensitive Amine Oxidase: Current Status and Perspectives

Abstract

Semicarbazide-sensitive amine-oxidase (SSAO) is present in various human tissues and in plasma. Oxidative deamination of short-chain aliphatic amines is catalyzed by this enzyme to afford the corresponding aldehydes, ammonia and hydrogen peroxide. Methylamine and aminoacetone have been recognized to be physiological substrates for SSAO. There are several pathological states where increased serum SSAO activity have been found, such as diabetes mellitus, congestive heart failure, multiple types of cerebral infarction, uraemia, and hepatic cirrhosis. The role of SSAO in pathophysiology of diabetes has been most extensively investigated. The elevated formation of the potentially cytotoxic products of the enzyme may contribute to the endothelial injury of blood vessels, resulting in the early development of severe atherosclerosis; it may also contribute to the pathogenesis of diabetic angiopathy. It is now suggested that SSAO inhibitors may prevent the development of atherosclerosis and diabetic complications as well. Inhibitors can be conveniently subdivided into the main groups of hydrazine derivatives, arylalkylamines, propenyl- and propargylamines, oxazolidinones, and haloalkylamines. Of them, aryl(alkyl)hydrazines, and 3-halo-2-phenylallylamines are generally very strong SSAO inhibitors. Most of these inhibitors of SSAO have been originally developed for other purposes, or they are simple chemical reagents with highly reactive structural element(s); these compounds have not been able to fulfil all criteria of high potency, selectivity, and acceptable toxicity. New potent compounds with selectivity and low toxicity are needed, which may prove useful tools for understanding the roles and function of SSAO, or they may even be valuable substances for treatment of various diseases.

Anti-Inflammatory Effects of LJP 1586 [Z-3-Fluoro-2-(4-methoxybenzyl)allylamine Hydrochloride], an Amine-Based Inhibitor of Semicarbazide-Sensitive Amine Oxidase Activity

“…Endogenous substrates for SSAO include methylamine, formed from adrenaline and creatine metabolism, and aminoacetone, a product of amino acid catabolism. The active enzyme is a dimer and exists as both a type II transmembrane protein and in soluble form in plasma (for reviews see Boomsma et al, 2003;Yu et al, 2003, Matyus et al, 2004O'Sullivan et al, 2004). Experiments with genetically modified mice have demonstrated that the transmembrane form is the sole source of circulating plasma SSAO (Stolen et al, 2004).…”

Semicarbazide-sensitive amine oxidase and kidney disease

“…The inhibitors described during the last decade represent various structural scaffold-hydrazine derivatives, arylalkylamines, propenyl-and propargylamines, oxazolidinones, haloalkylamines, 1,3,4-oxadiazines, 4,5,6,7-tetrahydroimidazo [4,5-c]pyridines, carbox(thi)amides, sulfonamides, and thiazole derivatives (18,19,58,59). Although all these structures are highly hydrophobic small aryl-alkylamine molecules, all of them are potent irreversible inhibitors that interact with the topaquinone cofactor through a covalent bond.…”

“…However, the specificity of the mechanism of action remains open to question. In general, they were developed as MAO inhibitors and exhibit cross-reactivity with other amine oxidases (58). Few inhibitors have undergone extensive selectivity analyses against SSAO compared with MAO-A and MAO-B (57,77).…”

Synthesis of ortho-Functionalized 4-Aminomethylpyridazines as Substrate-Like Semicarbazide-Sensitive Amine Oxidase Inhibitors

“…Among the various approaches, the development of 4-aminopyridines as substrate-like inhibitors (see above) deserves attention, as these compounds do not possess the frequently observed toxicity of classical carbonyl reagents such as hydrazine derivatives, which are known to irreversibly block the enzyme by forming a covalent bond with the topaquinone subunit of SSAO. 3,4) Starting from the structural motif of Bertini's 4aminomethylpyridines ("aza-benzylamines"), 2) we now took the aza-bioisosterism principle one step further, as we envisaged replacement of the pyridine ring by a pyridazine ring. It is well known that exchange of a pyridine by a diazine (and especially by a pyridazine) can significantly alter the physicochemical properties of a compound (lower basicity, higher dipole moment, increased water solubility), as demonstrated, for instance, with some aza analogues of the pyridocarbazole alkaloids.…”