SSAO InhibitorsIn this field of research, the group of N. Haider collaborates with the Semmelweis University of Budapest/Hungary (Prof. Péter Mátyus, Prof. Kalman Magyar) and with the biotech company, BioTie (Turku/Finland).
The enzyme, semicarbazide-sensitive amine oxidase (SSAO; EC 188.8.131.52) is present in various mammalian, including human, tissues (particularly high amounts are found in smooth muscle cells of blood vessels) and in plasma. Oxidative deamination of short-chain aliphatic amines (e.g. benzylamine, methylamine, aminoacetone, etc.) is catalyzed by this enzyme, with the production of the corresponding aldehydes, ammonia and hydrogen peroxide. Increased activity of SSAO was found in both insuline-dependent (IDDM) and non-insuline-dependent diabetic patients and diabetic animals. 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, or may be involved in the pathogenesis of diabetic angiopathy. Previous clinical studies have revealed a significant positive correlation between SSAO activity and some risk factors of atherosclerosis (obesity, serum cholesterol and triglyceride levels, etc.) both in diabetic and control subjects. These observations suggest that SSAO inhibitors may prevent the development of atherosclerosis and diabetic complications, as well. All these findings have stimulated the search for effective, non-toxic SSAO enzyme inhibitors. Although a number of studies have been performed in various species, data about selective and potent inhibitors for the human forms of the enzyme are scarce. Published data have also revealed considerable species differences in inhibitor sensitivity of SSAO enzymes. In addition, different sensitivity of plasma and tissue forms of SSAO were registered in the same species, as well.
The majority of known inhibitors of SSAO are hydrazine compounds, e.g. semicarbazide, hydralazine, procarbazine etc., some of them are rather toxic. Also mexiletine analogs were reported to inhibit SSAO in rat brain, heart and lung with moderate potency. The aim of our efforts in this field is to synthesize new inhibitors of human SSAO with good activity and selectivity (with respect to MAO inhibition). Target structures comprise mexiletine-derived scaffolds as well as heteroaromatic lactams and aminomethyl-hetarenes related to the model compound, B-24. In-vitro and in-vivo evaluation of biological activity is performed by pharmacologists at the Semmelweis university in Hungary and by our industrial partner, BioTie, in Finland.