Scientific literature describes that sumatriptan is metabolized by oxidative deamination of its dimethylaminoethyl residue by monoamine oxidase A (MAO A) and not by cytochrome P450 (CYP)‐mediated demethylation, as is usual for such structural elements. Using recombinant human enzymes and HPLC‐MS analysis, we found that CYP enzymes may also be involved in the metabolism of sumatriptan. The CYP1A2, CYP2C19, and CYP2D6 isoforms converted this drug into N ‐desmethyl sumatriptan, which was further demethylated to N , N ‐didesmethyl sumatriptan by CYP1A2 and CYP2D6. Otherwise, sumatriptan and its two desmethyl metabolites were metabolized by recombinant MAO A but not by MAO B to the corresponding acetaldehyde, with sumatriptan being only a poor substrate for MAO A compared to the N ‐demethylated and the N , N ‐didemethylated derivatives.
Amine oxidase copper containing 3 (AOC3), also known as plasma amine oxidase, semicarbazide-sensitive amine oxidase, or vascular adhesion protein-1, catalyzes the oxidative deamination of primary amines to aldehydes using copper and a quinone as cofactors. Because it is involved in the transmigration of inflammatory cells through blood vessels into tissues, AOC3 is thought to play an important role in inflammatory diseases. Therefore, inhibitors of this enzyme could lead to new therapeutics for the treatment of inflammation-related diseases. Recently, 6-(5-phenyl-2H-tetrazol-2-yl) hexan-1-amine was found to be a tight-binding substrate of AOC3. To obtain novel inhibitors of the enzyme, the amino group of this substrate was replaced with functional groups that occur in known AOC3 inhibitors, such as hydrazide or glycine amide moieties. In addition, derivatives of the compounds obtained in this way were prepared. The obtained hydrazide 5, which proved to be the most effective, was subjected to further structural modifications. Selected hydrazides were evaluated for selectivity toward some other amine oxidases.
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