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

作者：Butini Stefania; Brindisi Margherita; Gemma Sandra; Minetti Patrizia^*; Cabri Walter; Gallo Grazia; Vincenti Silvia; Talamonti Emanuela; Borsin Franco; Caprioli Antonio; Stasi Maria Antonietta; Di Serio Stefano; Ros Sindu; Borrelli Giuseppe; Maramai Samuele; Fezza Filomena; Campiani Giuseppe; Maccarrone Mauro

来源：Journal of Medicinal Chemistry, 2012, 55(15): 6898-6915.

DOI：10.1021/jm300689c

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-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-z), functionalized by specific polyethereal lateral chains and fluorinated aromatic rings.

• 出版日期2012-8-9