Drug Design and Discovery Center, Laboratoire de Chimie Biologique Structurale, Member of NARILIS, Facultés Universitaires Notre-Dame de Paix, Namur, Belgium.
Eur J Med Chem. 2011 Dec;46(12):6104-11. doi: 10.1016/j.ejmech.2011.09.042. Epub 2011 Oct 8.
Previous studies on 5H-indeno[1,2-c]pyridazin-5-one derivatives as inhibitors of MAO-B revealed that it was possible to increase the MAO-B inhibitory potency of 5H-indeno[1,2-c]pyridazin-5-ones by substituting the central heterocycle in the 3-position or C-8 with lipophilic groups which occupy the substrate cavity or the entrance of the binding site, respectively. Here, four new 5H-indeno[1,2-c]pyridazin-5-one derivatives containing lipophilic groups at both positions were synthesized and their inhibitory potency against human monoamine oxidase A and B were evaluated. Selectivity of these compounds against IDO and TDO, two enzymes sharing substrate similarity with MAO and involved in the serotonergic and kynurenine pathways was also studied. All compounds showed higher activity and selectivity against MAO-B, the most effective one being 3-methyl-8-meta-chlorobenzyloxy-5H-indeno[1,2-c]pyridazin-5-one (9a) which was shown to be a competitive inhibitor with a K(i) value of 0.11 μM. Replacing the methyl group in the 3-position with a meta-CF(3)-phenyl group (7a, 7b and 7c) abolished the inhibitory potency against MAO-B. Indeed, the substitution of the 5H-indeno[1,2-c]pyridazin-5-one core in the 3-position dramatically influences the MAO-inhibiting properties of these compounds. Molecular docking studies of 9a within MAO-B suggest that the 5H-indeno[1,2-c]pyridazin-5-one scaffold is well stabilized into the substrate cavity with the meta-chlorobenzyloxy side chain extending towards a rather hydrophobic pocket at the entrance cavity.
先前的研究表明，5H-茚并[1,2-c]哒嗪-5-酮衍生物作为 MAO-B 的抑制剂，通过在 3 位或 C-8 位用取代的中央杂环取代亲脂性基团，可以增加 5H-茚并[1,2-c]哒嗪-5-酮的 MAO-B 抑制活性，分别占据底物腔或结合位点的入口。在这里，合成了四个新的 5H-茚并[1,2-c]哒嗪-5-酮衍生物，它们在两个位置都含有亲脂性基团，并评估了它们对人单胺氧化酶 A 和 B 的抑制活性。这些化合物对 IDO 和 TDO 的选择性也进行了研究，IDO 和 TDO 是与 MAO 具有相似底物相似性的两种酶，参与色氨酸和犬尿氨酸途径。所有化合物对 MAO-B 的活性和选择性均较高，最有效的化合物为 3-甲基-8-间氯苄氧基-5H-茚并[1,2-c]哒嗪-5-酮（9a），它是一种竞争性抑制剂，K(i)值为 0.11 μM。用间-CF3-苯取代 3-位上的甲基（7a、7b 和 7c），则消除了对 MAO-B 的抑制活性。实际上，3-位上 5H-茚并[1,2-c]哒嗪-5-酮核心的取代极大地影响了这些化合物的 MAO 抑制特性。9a 在 MAO-B 中的分子对接研究表明，5H-茚并[1,2-c]哒嗪-5-酮支架很好地稳定在底物腔中，间氯苄氧基侧链伸向入口腔中的一个相当疏水的口袋。
