Synthesis and Monoamine Oxidase Inhibitory Activity of New Pyridazine-, Pyrimidine- and 1,2,4-Triazine-Containing Tricyclic Derivatives

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• 作者：Andrea Carotti ; Marco Catto ; Francesco Leonetti ; Francesco Campagna ; Ramó ; n Soto-Otero ; Estefan&iacute ; a Mé ; ndez-Á ; lvarez ; Ulrike Thull ; Bernard Testa ; Cosimo Altomare
• 刊名：Journal of Medicinal Chemistry
• 出版年：2007
• 出版时间：November 1, 2007
• 年：2007
• 卷：50
• 期：22
• 页码：5364 - 5371
• 全文大小：212K
• 年卷期：v.50,no.22(November 1, 2007)
• ISSN：1520-4804

文摘

A number of condensed azines, mostly belonging to the families of indeno-fused pyridazines (1), pyrimidines(2, 3), and 1,2,4-triazines (4, 5), were synthesized and evaluated in vitro as monoamine oxidase (MAO) Aand B inhibitors. Most of them showed higher inhibition potency toward MAO-B, the most effective onebeing 3-(3-nitrophenyl)-9H-indeno[1,2-e] [1,2,4]triazin-9-one (4c), which displayed an IC₅₀ value of 80 nMand proved to be 10-fold more potent than its [2,1-e] fusion isomer 5. Replacing the 3-phenyl group of theknown indeno[1,2-c]pyridazin-5-one MAO-B inhibitors with a flexible phenoxymethyl group enhanced theinhibitory potency. The inhibition data highlighted the importance of the aza-heterocyclic scaffold in affectingthe MAO isoform selectivity. The 3-phenyl derivatives with type 1, 4, and 5 scaffolds were inhibitors ofMAO-B with little or no MAO-A effect, whereas 2- or 3-phenyl derivatives of type 2 and 3 pyrimidine-containing fusion isomers inhibited both isoenzymes with a structure-dependent preference toward MAO-A.