European Research Centre for Drug Discovery and Development (NatSynDrugs), Università degli Studi di Siena , Via Aldo Moro 2, 53100 Siena, Italy.
J Med Chem. 2012 Aug 9;55(15):6898-915. doi: 10.1021/jm300689c. Epub 2012 Jul 26.
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.
脂肪酸酰胺水解酶（FAAH，EC3.5.1.99）是代谢内源性大麻素脂肪酸酰胺的主要酶。FAAH 的失活可以促进疼痛和焦虑的有益效果，而不会产生 1 型大麻素受体激动剂的副作用。为了发现新的选择性 FAAH 抑制剂，我们开发了一系列具有功能化杂芳基骨架的化合物（5a-u）。特别是，5c 和 5d 被鉴定为极有效的、非竞争性的和可逆的 FAAH 抑制剂，具有显著的选择性特征，并且与 hERG 通道没有相互作用。5c、5d 和 5n 在低于诱导纹状体和边缘刻板行为或抗焦虑活性的剂量下表现出体内镇痛活性，因此表明它们有可能成为最佳的临床前候选药物。为了改善 5d 的药代动力学性质和代谢稳定性，我们开发了一组纳摩尔可透析 FAAH 抑制剂（5v-z），它们通过特定的聚醚侧链和氟化芳环进行了功能化。
