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 x 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 determinations with CAOs from mammals.
Bertini
Vincenzo
V
Dipartimento di Chimica e Tecnologie Farmaceutiche e Alimentari, Università di Genova, Via Brigata Salerno, 16147 Genova, Italy. bertini@dictfa.unige.it
Buffoni
Franca
F
Ignesti
Giovanni
G
Picci
Nevio
N
Trombino
Sonia
S
Iemma
Francesca
F
Alfei
Silvana
S
Pocci
Marco
M
Lucchesini
Francesco
F
De Munno
Angela
A
D006631:Amine Oxidase (Copper-Containing) / Q000037:antagonists & inhibitors* / Q000737:chemistry; D000818:Animals; D007700:Kinetics; D007928:Lethal Dose 50; D051379:Mice; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D013329:Structure-Activity Relationship; D023382:Toxicity Tests, Acute
D011725:Pyridines; D006631:Amine Oxidase (Copper-Containing)