Discovery of Potent Inhibitors of Human and Mouse Fatty Acid Amide Hydrolases

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• 作者：Stefania Butini ; Margherita Brindisi ; Sandra Gemma ; Patrizia Minetti ; Walter Cabri ; Grazia Gallo ; Silvia Vincenti ; Emanuela Talamonti ; Franco Borsini ; Antonio Caprioli ; Maria Antonietta Stasi ; Stefano Di Serio ; Sindu Ros ; Giuseppe Borrelli ; Samuele Maramai ; Filomena Fezza ; Giuseppe Campiani ; Mauro Maccarrone
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：August 9, 2012
• 年：2012
• 卷：55
• 期：15
• 页码：6898-6915
• 全文大小：697K
• 年卷期：v.55,no.15(August 9, 2012)
• ISSN：1520-4804

文摘

Fatty acid amide hydrolase (FAAH, EC 3.5.1.99) is the main enzyme catabolizing endocannabinoid fatty acid amides. FAAH inactivation promotes beneficial effects upon pain and anxiety without the side effects accompanying agonists of type-1 cannabinoid receptors. Aiming at discovering new selective FAAH inhibitors, we developed a series of compounds (5a鈥?b>u) characterized by a functionalized heteroaromatic scaffold. Particularly, 5c and 5d were identified as extremely potent, noncompetitive, and reversible FAAH inhibitors endowed with a remarkable selectivity profile and lacking interaction with the hERG channels. In vivo antinociceptive activity was demonstrated for 5c, 5d, and 5n at a dose much lower than that able to induce either striatal and limbic stereotypies or anxiolytic activity, thus outlining their potential to turn into optimum preclinical candidates. Aiming at improving pharmacokinetic properties and metabolic stability of 5d, we developed a subset of nanomolar dialyzable FAAH inhibitors (5v鈥?b>z), functionalized by specific polyethereal lateral chains and fluorinated aromatic rings.