Therapeutic Targeting of Carotid Body Chemoreflex for Sleep Disordered Breathing

颈动脉体 Chemoreflex 治疗睡眠呼吸障碍的靶向治疗

• 批准号: 8753684
• 负责人: DAVID L. MCCORMICK
• 金额: $ 166.37万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-22 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8753684
• 关键词: Affect; Animal Model; Apnea; Arrhythmia; Atrial Fibrillation; Bioavailable; Biological Assay; Biological Availability; Biological Factors; Blood Pressure; Breathing; Canis familiaris; Carotid Body; Cells; Central Sleep Apnea; Chemicals; Clinical; Clinical Trials; Comorbidity; Computer Simulation; Congestive Heart Failure; Continuous Positive Airway Pressure; Cystathionine; Data; Disease; Dose; Drug Formulations; Drug Kinetics; Drug toxicity; Enzymes; Exhibits; Functional disorder; Funding; Generations; Glutamate Decarboxylase; Health; Homocysteine; Homocystine; Human; Hydrogen Sulfide; Hypersensitivity; Hypertension; Hypoxia; In Vitro; Investigational Drugs; Investigational New Drug Application; Laboratories; Lead; Libraries; Lyase; Mediator of activation protein; Medical; Medicine; Metabolic; Metabolism; No-Observed-Adverse-Effect Level; Obstructive Sleep Apnea; Oral; Organ; Pathology; Patients; Pharmacologic Substance; Pharmacy (field); Phase; Plasma; Play; Population; Prevention; Production; Program Development; Property; Proteins; Published Comment; Rattus; Reflex action; Refractory; Research Design; Resistance; Rodent Model; Role; Safety; Sleep; Sleep Apnea Syndromes; Structure; Sympathetic Nervous System; Testing; Therapeutic Intervention; Toxic effect; Toxicology; X-Ray Crystallography; alternative treatment; base; cytotoxicity; design; drug candidate; endothelial dysfunction; frontier; in vivo; inhibitor/antagonist; iterative design; pre-clinical; prevent; response; scale up; screening; small molecule; therapeutic target; treatment strategy

DESCRIPTION (provided by applicant): Sleep disordered breathing (SDB) is a major health problem affecting an estimated 18 million people in the USA alone. Clinical manifestations of SDB include obstructive sleep apnea (OSA), central apnea and periodic breathing. While treatment options for central apnea and periodic breathing are limited, continuous positive airway pressure (CPAP) is the current choice of treatment for OSA. However, substantial populations of OSA patients are refractory to CPAP treatment. Consequently, there is an absolute need for developing alternative and adjunctive strategies for treating SDB. A heightened carotid body chemo reflex plays a substantial role in SDB pathophysiology - both as mediator of the disease and the downstream pathology caused by intermittent hypoxia. Thus, preventing carotid body hypersensitivity is a potential therapeutic intervention for treating SDB and its effects. Our recent studies suggest that enhanced -¿-lyase (CSE) catalyzed hydrogen sulfide (H2S) generation contributes to carotid body hypersensitivity and L-propargylglycine (L-PAG), an inhibitor of CSE enzyme reduces carotid body hypersensitivity and normalizes breathing in rodent models of SDB. Based on these findings the current proposal seeks CADET-2 funding to pursue a preclinical development program in which L-PAG is chemically optimized for efficacy, potency, selectivity, safety, and desirable pharmacological and pharmaceutical properties, culminating in a new candidate medicine suitable for treating SDB. AIM 1 proposes to develop highly selective and potent small molecule inhibitors of CSE as drug candidates for SDB. Studies in AIM 2 perform in vivo screening of compounds for their efficacy, potency, and selectivity for on-target effects on breathing with apnea in rodent models. AIM 3 establishes preclinical toxicology, pharmacokinetics and metabolism. AIM 4 will facilitate filing an investigational new drug (IND) application with the US FDA. Successful and safe pharmacological inhibition of hyperactive chemo reflex has the potential to open up an entirely new frontier of medical treatment for alleviating SDB with apneas in CPAP resistant OSA, central apnea and periodic breathing patients. (End of Reviewers' Comments)

描述（由申请人提供）：睡眠呼吸障碍（SDB）是一个主要的健康问题，仅在美国就影响着大约1800万人。SDB的临床表现包括阻塞性睡眠呼吸暂停（OSA）、中枢性呼吸暂停和周期性呼吸。虽然中枢性呼吸暂停和周期性呼吸的治疗选择有限，但持续气道正压通气（CPAP）是目前治疗OSA的选择。然而，大量OSA患者对CPAP治疗是难治的。因此，绝对需要开发用于治疗SDB的替代性和预防性策略。增强的颈动脉体化学反射在SDB病理生理学中起重要作用-作为疾病的介质和由间歇性缺氧引起的下游病理学。因此，预防颈动脉体超敏反应是治疗SDB及其效应的潜在治疗干预。我们最近的研究表明，增强型β-裂解酶（CSE）催化的硫化氢（H2S）生成有助于颈动脉体超敏反应，而CSE酶抑制剂L-炔丙基甘氨酸（L-PAG）可降低颈动脉体超敏反应并使SDB啮齿动物模型的呼吸正常化。基于这些发现，目前的提案寻求CADET-2资金，以进行临床前开发计划，其中L-PAG在功效，效力，选择性，安全性和理想的药理学和药学特性方面进行化学优化，最终获得适合治疗SDB的新候选药物。目的1提出开发高选择性和有效的CSE小分子抑制剂作为SDB的候选药物。AIM 2中的研究在啮齿动物模型中对化合物进行了体内筛选，以确定其对呼吸暂停的有效性、效力和靶向效应的选择性。目的3建立临床前毒理学，药代动力学和代谢。AIM 4将有助于向美国FDA提交研究性新药（IND）申请。成功和安全的药物抑制过度活跃的化学反射有可能开辟一个全新的前沿医学治疗，以减轻睡眠呼吸障碍与呼吸暂停的CPAP抵抗OSA，中枢性呼吸暂停和周期性呼吸患者。 (End评论员评论）