Inhibitors of Fatty Acid Amide Hydrolase (FAAH)

描述(由申请人提供)：详细介绍了脂肪酸酰胺水解酶(FAAH)的有效和选择性抑制剂的开发，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。这些研究将不仅提供这些抑制剂的体外表征，而且还将提供它们的体内评价(疼痛、睡眠和炎症)和表征(PK特性、代谢)。他们将阐明内源性油酰胺和花生胺的作用，确立FAAH作为治疗靶点的全部用途，并为疼痛、睡眠障碍和包括接触性皮炎和多发性硬化症在内的慢性炎症性疾病的治疗提供一些首批临床候选药物。我们的研究非常广泛，提供了一流的选择性、特效性、可逆性和竞争性的FAAH抑制剂，并确定了影响抑制剂设计的关键结构特征。这些研究不仅提供了一套有效的？-酮杂环FAAH抑制剂，而且解决了在之前的赠款期间作为具体目标提出的所有目标。同时进行的效力(针对FAAH)和选择性(ABPP蛋白质组范围的筛选)优化提供了没有显著脱靶活性的选择性抑制剂，包括其他潜在的酶靶点、常见的P450代谢酶或HERG，并且在所有慢性和神经病理性疼痛和炎症模型中显示出有效的体内活性。这些研究将继续进行，它们将扩展到新的FAAH抑制剂类别，它们的体外和体内优化使用基础化学、生化和药理学工具，目的是提供第一个可逆的抑制剂用于临床检查。此外，还将进行研究，以确定每个脂肪酸酰胺信号分子的作用部位和内源性作用，并准备和利用筛选文库来注释每一个未鉴定的丝氨酸水解酶。

DESCRIPTION (provided by applicant): The development of potent and selective 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. The studies will provide not only the in vitro characterization of the inhibitors, but also their in vivo evaluation (pain, sleep, and inflammation) and characterization (PK properties, metabolism). They will clarify the role of endogenous oleamide and anandamide, establish the full scope of the utility of FAAH as a therapeutic target, and provide some of the first clinical candidates for the treatment of pain, sleep disorders, and chronic inflammatory diseases including contact dermatitis, and multiple sclerosis. Our studies have been extensive, providing the first class of selective, exceptionally potent, reversible and competitive inhibitors of FAAH and defining key structural features that impact inhibitor design. These studies not only provided a set of efficacious ?-ketoheterocycle FAAH inhibitors, but they addressed all the objectives set forth as specific aims in the prior grant period. The simultaneous potency (against FAAH) and selectivity (ABPP proteome-wide screening) optimizations provided selective inhibitors that display no significant off target activity including other potential enzyme targets, common P450 metabolizing enzymes, or hERG, and that exhibit efficacious in vivo activity in all models of chronic and neuropathic pain and inflammation. The continuation of these studies, their extensions to new classes of FAAH inhibitors, their in vitro and in vivo optimization using fundamental chemical, biochemical, and pharmacological tools, will be conducted with the intention of providing the first reversible inhibitors for examination in the clinic. In addition, studies to define the sites of action and endogenous role of every fatty acid amide signaling molecule and to prepare and utilize a screening library to annotate every uncharacterized serine hydrolase will be conducted.