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）的有效和选择性抑制剂的开发，FAAH是负责降解油酰胺（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。这些研究不仅将提供抑制剂的体外表征，还将提供其体内评价（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四烯酸酰胺的作用，建立FAAH作为治疗靶点的全部效用范围，并为治疗疼痛，睡眠障碍和慢性炎性疾病（包括接触性皮炎和多发性硬化症）提供一些首批临床候选药物。我们的研究是广泛的，提供了第一类选择性的，非常有效的，可逆的和竞争性的FAAH抑制剂，并定义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，但他们解决了所有的目标提出的具体目标，在前一个赠款期。同时的效力（针对FAAH）和选择性（ABPP蛋白质组范围筛选）优化提供了选择性抑制剂，其不显示显著的脱靶活性，包括其他潜在的酶靶标、常见的P450代谢酶或hERG，并且在慢性和神经性疼痛和炎症的所有模型中显示有效的体内活性。这些研究的继续，其扩展到新类别的FAAH抑制剂，其在体外和体内优化使用基本的化学，生物化学和药理学工具，将进行的目的是提供第一个可逆的抑制剂在临床上检查。 此外，将进行研究以确定每个脂肪酸酰胺信号分子的作用位点和内源性作用，并制备和利用筛选文库来注释每个未表征的丝氨酸水解酶。 公共卫生相关性：脂肪酸酰胺水解酶（FAAH）抑制剂的开发和表征将被追求，并可能为慢性和神经性疼痛提供新的治疗方法。新的内源性信号脂肪酸酰胺及其作用位点的发现和表征将提供对它们的生理作用的基本理解，以及在一系列疾病（睡眠、进食、焦虑）中进行治疗干预的新机会。每一个未注释的丝氨酸水解酶的选择性和有效的抑制剂的发展将有利于描绘其内源性作用和评价作为新的治疗靶点。

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. PUBLIC HEALTH RELEVANCE: The development and characterization of inhibitors of the enzyme fatty acid amide hydrolase (FAAH) will be pursued and could provide a new treatment for chronic and neuropathic pain. The discovery and characterization of new endogenous signaling fatty acid amides and their sites of action would provide a fundamental understanding of their physiological role and new opportunities for therapeutic intervention in a range of disorders (sleep, feeding, anxiety). The development of selective and potent inhibitors for each unannotated serine hydrolase will facilitate the delineation of their endogenous role and their evaluation as new therapeutic targets.