Discovery of NaV1.7 Inhibitors for the Treatment of Pain

发现用于治疗疼痛的 NaV1.7 抑制剂

• 批准号: 9761823
• 负责人: John Vincent Mulcahy
• 金额: $ 22.62万
• 依托单位: SITEONE THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-01 至 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9761823
• 关键词: Action Potentials; Adverse drug effect; Afferent Neurons; Analgesics; Biological Assay; Caliber; Cardiac; Chemotherapy-induced peripheral neuropathy; Chronic; Development; Dissociation; Dose; Dose-Limiting; Drug usage; Exhibits; Genetic; Genetic Diseases; Heart; Human; Hyperalgesia; Hypersensitivity; Intravenous; Ion Channel; Kinetics; Lead; Ligands; Mechanics; Messenger RNA; Modeling; Motor; Motor Neurons; Muscle; Neuraxis; Neurons; Neuropathy; Nociception; Paclitaxel; Pain; Pain management; Patients; Perioperative; Peripheral; Peripheral Nervous System Diseases; Pharmaceutical Preparations; Pharmacology; Phase I Clinical Trials; Plasma; Platinum; Polymorph; Preparation; Presynaptic Terminals; Protein Isoforms; Proteins; Rattus; Respiratory Diaphragm; Rodent; Route; Safety; Selection Criteria; Sensory; Series; Shock; Signal Transduction; Site; Sodium Channel; Sodium Chloride; Spinal Ganglia; Structure of phrenic nerve; Symptoms; Testing; Tetrodotoxin; Therapeutic; Toxic effect; Treatment Protocols; Work; base; cancer therapy; candidate selection; chemotherapeutic agent; chemotherapy induced neuropathy; clinical development; design; diabetic; dorsal horn; experience; first-in-human; genotoxicity; in vivo; inflammatory pain; inhibitor/antagonist; lead candidate; mechanical allodynia; non-opioid analgesic; nonhuman primate; novel; optimal treatments; pain behavior; pain reduction; pain sensation; pain sensitivity; pain signal; painful neuropathy; pre-clinical; preclinical development; prevent; programs; respiratory; safety study; screening; security critical system; side effect; small molecule inhibitor; subcutaneous; taxane; therapeutic target; transmission process; voltage

PROJECT SUMMARY The objective of our program is to develop a safe and effective nonopioid analgesic for the treatment of neuropathic pain, such as pain associated with chemotherapy-induced peripheral neuropathy, that targets an isoform of the voltage-gated sodium ion channel, NaV1.7. Voltage-gated sodium channels are involved in the transmission of nociceptive signals from their site of origin in the peripheral terminals of DRG neurons to the synaptic terminals in the dorsal horn. Ten mammalian isoforms exist, NaV1.1–1.9 and NaX. NaV1.7 is the most abundant tetrodotoxin-sensitive sodium channel in small diameter myelinated and unmyelinated afferents, where it has been shown to modulate excitability and set the threshold for action potentials. Humans lacking functional NaV1.7 due to a rare genetic condition are unable to experience almost all types of pain. Efforts to develop systemic inhibitors of NaV1.7 have been complicated by the challenge of achieving selectivity over other NaV isoforms expressed in the diaphragm, phrenic nerve, heart and central nervous system that are critical for safety. SiteOne Therapeutics has discovered a series of potent, state-independent NaV1.7 inhibitors that exhibit >1000-fold selectivity over other human isoforms. Work conducted under this program will support advancement of a lead candidate into clinical development as a therapeutic for neuropathic pain.

项目总结