Inhibitors of Fatty Acid Amide Hydrolase (FAAH)

描述（由申请人提供）：详细描述了脂肪酸酰胺水解酶（FAAH）（负责降解油酰胺（一种内源性睡眠诱导脂质）和花生四烯酸酰胺（大麻素和香草素受体的内源性配体）的酶）的异常强效抑制剂的开发。在广泛合作的帮助下，不仅可以提供抑制剂的体外表征，还可以提供其体内评估（动物疼痛、睡眠、焦虑和多发性硬化模型）和表征（PK特性，代谢），这些研究将阐明内源性油酰胺和花生四烯酸酰胺的作用，建立FAAH作为治疗靶点的效用，并潜在地提供用于治疗睡眠障碍、焦虑、癫痫、疼痛、癌症、帕金森和亨廷顿病、中风和/或多发性硬化症的治疗剂。在5年的时间内进行了广泛的初步研究，提供了第一类非常有效的竞争性FAAH抑制剂，并定义了影响未来抑制剂设计的关键结构特征。这些研究已经提供了一组α-酮杂环FAAH抑制剂，其Ki低于200 pM，并且比相应的三氟甲基酮的效力高100 -1000倍。

DESCRIPTION (provided by applicant): The development of exceptionally potent inhibitors of fatty acid amide hydrolase (FAAH), the enzyme responsible for the degradation of oleamide (an endogenous sleep-inducing lipid) and anandamide (an endogenous ligand for cannabinoid and vanilloid receptors), is detailed. With the help of an extensive set of collaborations that will provide not only the in vitro characterization of the inhibitors, but also their in vivo evaluation (animal pain, sleep, anxiety, and multiple sclerosis models) and characterization (PK properties, metabolism), the studies will clarify the role of endogenous oleamide and anandamide, establish the utility of FAAH as a therapeutic target, and potentially provide therapeutic agents for the treatment of sleep disorders, anxiety, epilepsy, pain, cancer, Parkinson's and Huntington's disease, stroke, and/or multiple sclerosis. Preliminary studies conducted over a period spanning 5 years have been extensive, providing the first class of exceptionally potent, competitive inhibitors of FAAH and defining key structural features that impact future inhibitor design. These studies have provided a set of a-ketoheterocycle FAAH inhibitors with Ki's that drop below 200 pM and that are l00-1000 times more potent than the corresponding trifluoromethyl ketones.