Inhibitors of Fatty Acid Amide Hydrolase (FAAH)

脂肪酸酰胺水解酶 (FAAH) 抑制剂

• 批准号: 8628824
• 负责人: DALE L BOGER
• 金额: $ 41.45万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-30 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8628824
• 关键词: Address; Adverse effects; Agonist; Amides; Anxiety; Biochemical; Cannabinoids; Chemicals; Chronic; Clinic; Clinical; Contact Dermatitis; Cytochrome P450; Dependence; Development; Disease; Dose; Enzyme Inhibitor Drugs; Enzyme Inhibitors; Enzymes; Evaluation; Exhibits; Fatty Acids; Food; Grant; Human Genome; In Vitro; Inflammation; Inflammatory; Intention; Libraries; Ligands; Lipids; Metabolism; Modeling; Multiple Sclerosis; Neuropathy; Opioid; PTGS2 gene; Pain; Pharmaceutical Chemistry; Pharmacologic Substance; Physiological; Property; Proteins; Proteome; Role; Science; Serine Hydrolase; Signal Transduction; Signaling Molecule; Site; Sleep; Sleep Disorders; Therapeutic; Therapeutic Intervention; Ventilatory Depression; Work; anandamide; bropirimine; cannabinoid receptor; capsaicin receptor; chronic neuropathic pain; chronic pain; desensitization; design; drug discovery; fatty acid amide hydrolase; feeding; in vivo; inhibitor/antagonist; innovation; motor control; new therapeutic target; oleylamide; public health relevance; receptor; screening; therapeutic target; tool

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.

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是负责降解油酰胺（一种内源性睡眠诱导脂质）和anandamide（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，还将提供其体内评估（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 anandamide 的作用，建立 FAAH 作为治疗靶点的完整用途范围，并为治疗疼痛、睡眠障碍和慢性炎症性疾病（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。我们的研究非常广泛，提供了第一类选择性、特别有效、可逆和竞争性的 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β-酮杂环FAAH抑制剂，而且还解决了在先前资助期间作为具体目标提出的所有目标。同时效力（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，这些抑制剂没有表现出显着的脱靶活性，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性疼痛和炎症模型中表现出有效的体内活性。这些研究的继续、对新型 FAAH 抑制剂的扩展、使用基本化学、生化和药理学工具的体外和体内优化，将旨在提供第一个用于临床检查的可逆抑制剂。 此外，还将进行研究以确定每种脂肪酸酰胺信号分子的作用位点和内源性作用，并准备和利用筛选文库来注释每种未表征的丝氨酸水解酶。