Control of Arthritic Pain by Inhibition of TRPA1 Activity

通过抑制 TRPA1 活性控制关节炎疼痛

• 批准号: 8592843
• 负责人: Jeff Mark Herz
• 金额: $ 31.34万
• 依托单位: ALGOMEDIX, INC.
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-10 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8592843
• 关键词: Address; Adverse effects; Afferent Neurons; Age-Years; Agonist; Analgesics; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Arthritis; Biological Availability; C Fiber; Cells; Cessation of life; Chemicals; Chronic; Clinical; Degenerative polyarthritis; Development; Dose; Drug Design; Drug Interactions; Drug Kinetics; Drug usage; Equilibrium; Esthesia; Family member; Fiber; Future; Genetic; Goals; Health Care Costs; Hemorrhage; Human; Human Activities; Hyperalgesia; In Vitro; Inflammation; Ion Channel; Joints; Kinetics; Lead; Life; Ligands; Medical; Medicine; Modeling; Molecular; Molecular Target; Nerve Fibers; Neurons; Nociception; Nociceptors; Oral; Pain; Patients; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacology; Phase; Physiological; Play; Process; Program Development; Property; Rattus; Research; Safety; Sensory; Sensory Nerve Endings; Sensory Receptors; Signal Transduction; Small Business Innovation Research Grant; Source; Specificity; Spinal Ganglia; Staging; Structure; Structure-Activity Relationship; TRP channel; TRPV1 gene; Testing; Therapeutic; Therapeutic Agents; Toxicity Tests; afferent nerve; analog; animal efficacy; arthropathies; base; design; disability; efficacy testing; ganglion cell; gastrointestinal; in vitro Assay; in vivo; innovation; meetings; member; nerve injury; novel; novel strategies; novel therapeutic intervention; novel therapeutics; pain inhibition; programs; public health relevance; receptor; relating to nervous system; response; scaffold; small molecule

DESCRIPTION (provided by applicant): A safe and effective therapeutic for treatment of osteoarthritis (OA) represents a major unmet medical need. OA is the leading cause of disability in the US and pain is a predominant clinical feature. However, chronic use of non-steroidal anti-inflammatory drugs (NSAIDs) is associated with potentially life-threatening gastrointestinal bleeding and calculations estimate that about 100,000 patients are hospitalized annually for NSAID related GI complications and about 16,500 NSAID-related deaths occur among arthritis patients in the US each year, leading to $2 billion in health care costs. The goal of this proposal is to develop a novel therapeutic approach based a new molecular mechanism that targets a key molecule involved in nociceptive signaling from the joint. We propose to develop a novel, first-in-class therapeutic small molecule compound which is a functional antagonist of TRPA1 (Transient Receptor Potential, Subfamily A, member 1) for the treatment of OA pain. TRPA1-receptor/channels serve a highly specific function on sensory nerve fiber endings in the joint that detect and transmit the sensations of pain and hyperalgesia in response to inflammation and nerve injury. Since TRPA1 is one of the most important signal integrators for pain in sensory nociceptors in the joint, an antagonist of TRPA1 will function as a peripherally acting analgesic. Our innovative approach is based on development of novel therapeutic agent that will block nociceptive signals at the first stage of neural processing and does not involve CNS action. Algomedix employs a rational pharmacology approach and has already made substantial progress in the identification of novel, small molecule chemical antagonists of TRPA1 The long-term goal of this project is to identify orally available antagonists of TRPA1 that will block the excitation of the nociceptive afferent fibers present in the joint that are activated in OA. This approach is based upon genetic and in vivo pharmacologic evidence that modulation of TRPA1 activity will have therapeutic value. The aims are: AIM 1 will be to synthesize a group of 75 novel, structural analogs based upon newly discovered TRPA1 ligands using a novel scaffold. Synthetic medicinal chemistry and structure guided drug design efforts will be used to enhance lead potency and to further define structure-activity relationships (SAR). AIM 2 will be to define the potency and pharmacological of novel compounds on human and rat TRPA1. In AIM 3, the pharmacological selectivity for novel antagonists will be defined among members of the TRP superfamily using a panel of related TRP channels, including TRPV1, TRPV3, TRPM8 and several TRPC members. AIM 4 will pharmacologically characterize the activity of the new drug using cultured dorsal root ganglion neurons, which are the primary target cell for TRPA1, and AIM 5 will conduct in vitro ADME profiling for the top-ranked active compounds and determine pharmacokinetics using oral dosing. The final Phase 1 milestone is to deliver an advanced lead molecule and backup compounds that have all properties necessary for nomination to a full development program in Phase 2. The anticipated Phase 2 program will consist of animal efficacy testing in multiple OA models and conducting pharmacokinetic studies in multiple animal species using oral dosing to enable the filing of an IND.

描述（由申请人提供）：一种安全有效的治疗骨关节炎（OA）的药物，代表了一个主要的未满足的医疗需求。骨性关节炎是美国致残的主要原因，疼痛是主要的临床特征。然而，长期使用非甾体抗炎药（NSAIDs）与潜在的危及生命的胃肠道出血有关，据估计，每年约有10万名患者因非甾体抗炎药相关的胃肠道并发症住院，美国关节炎患者中每年约有16,500名非甾体抗炎药相关的死亡，导致20亿美元的医疗费用。这个提议的目标