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

The first substratelike, reversible inhibitors of different copper amine oxidases (CAOs) with IC50 (M) as low as 2.0 × 10-8 corresponding to derivatives of 4-aminomethylpyridine with alkoxy (1a−d), alkylthio (2a,b), and alkylamino (3a−e, 4a−j) groups in the positions 3 and 5 have been prepared and studied. The inhibitors 1a−d are active on benzylamine oxidase and semicarbazide-sensitive amine oxidase and are very selective with respect to diamine oxidase, lysyl oxidase, and monoamine oxidases. The inhibitors 2a,b are selective for benzylamine oxidase whereas 2a is also a new type of good substrate of diamine oxidase. The inhibitors 3a−e and 4a−j are substratelike, reversible, nonselective inhibitors of various CAOs including pea seedling amine oxidase and Hansenula polymorpha amine oxidase, whose enzymatic sites are known from X-ray structure determinations. The inhibitors 3b,c and 4b,c are excellent substratelike tools for studies correlating CAOs that afford crystals suitable for X-ray structure determi...