Inhibitors of Fatty Acid Amide Hydrolase (FAAH)

描述(由申请人提供)：详细介绍了特别有效的脂肪酸酰胺水解酶(FAAH)抑制剂的开发，FAAH是一种负责降解油酰胺(一种内源性睡眠诱导脂类)和花生胺(一种大麻和香草素受体的内源性配体)的酶。在一系列广泛合作的帮助下，这些研究将不仅提供这些抑制剂的体外特征，而且还提供它们的体内评估(动物疼痛、睡眠、焦虑和多发性硬化症模型)和特征(PK特性、代谢)，这些研究将阐明内源性油酰胺和山梨酰胺的作用，确立FAAH作为治疗靶点的效用，并有可能提供治疗睡眠障碍、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。在长达5年的时间里进行了广泛的初步研究，提供了第一类非常有效的、具有竞争力的FAAH抑制剂，并确定了影响未来抑制剂设计的关键结构特征。这些研究提供了一组a-酮杂环FAAH抑制剂，KI‘s降至200 pm以下，其效力是相应的三氟甲基酮的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.