Alkylamino derivatives of 4-aminomethylpyridine as inhibitors of copper-containing amine oxidases

The first substrate-like, reversible inhibitors of different copper containing amine oxidases (CAOs) with IC50(M) values up to 2.0x10-8 corresponding to derivatives of 4-aminomethylpyridine (12) with alkoxy, alkylthio and alkylamino groups in the positions 3 and 5 of the pyridine ring (Chart 1) have been prepared and studied. The 3,5-dialkoxy-4-aminomethylpyridines (1a-d) are active on porcine serum benzylamine oxidase (BAO) and tissular semicarbazide sensitive amine oxidase (SSAO) with IC50(M) between 1.5x10-7 and 5.0x10-6 and are very selective with respect to other CAOs such as diamine oxidase (DAO) and lysyl oxidase (LO), other than mitochondrial monoamine oxidases (MAO) A and B. They are suitable for in vitro and in vivo experiments also under oral administration. The 3,5-dialkylthio-4-aminomethylpyridines (2a,b) are selective inhibitors of BAO while 2a is also an interesting new type of good substrate of DAO. The 3,5-dialkylamino-4-aminomethylpyridines (3a-e) and 3-alkylamino-4-aminomethylpyridines (4a-j) are substrate-like, reversible, nonselective inhibitors of various CAOs including pea seedling amine oxidase (PSAO) and Hansenula polymorpha amine oxidase (HPAO) whose enzymatic sites are known from X-ray structure determinations (Kumar et al. Structure 1996, 4, 943; Li et al. Structure 1998, 6, 293). The inhibitors 3b,c and 4b,c, very active on BAO, DAO, and also PSAO and HPAO, are excellent substrate-like tools for studies correlating CAOs obtainable in crystalline form, idoneous for X-ray structure determinations, and CAOs from mammals.