Investigations on the 4-Quinolone-3-carboxylic Acid Motif. 7. Synthesis and Pharmacological Evaluation of 4-Quinolone-3-carboxamides and 4-Hydroxy-2-quinolone-3-carboxamides as High Affinity Cannabino

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• 作者：Claudia Mugnaini ; Antonella Brizzi ; Alessia Ligresti ; Marco Allarà ; Stefania Lamponi ; Federica Vacondio ; Claudia Silva ; Marco Mor ; Vincenzo Di Marzo ; Federico Corelli
• 刊名：Journal of Medicinal Chemistry
• 出版年：2016
• 出版时间：February 11, 2016
• 年：2016
• 卷：59
• 期：3
• 页码：1052-1067
• 全文大小：687K
• ISSN：1520-4804

文摘

4-Quinolone-3-carboxamide derivatives have long been recognized as potent and selective cannabinoid type-2 receptor (CB2R) ligands. With the aim to improve their physicochemical properties, basically aqueous solubility, two different approaches were followed, entailing the substitution of the alkyl chain with a basic replacement or scaffold modification to 4-hydroxy-2-quinolone structure. According to the first approach, compound 6d was obtained, showing slightly reduced receptor affinity (K_i = 60 nM) compared to the lead compound 4 (0.8 nM) but greatly enhanced solubility (400–3400 times depending on the pH of the medium). On the other hand, shifting from 4-quinolone to 4-hydroxy-2-quinolone structure enabled the discovery of a novel class of CB2R ligands, such as 7b and 7c, characterized by K_i < 1 nM and selectivity index [SI = K_i(CB1R)/K_i(CB2R)] > 1300. At pH 7.4, compound 7c resulted by 100-fold more soluble than 4.