Melanocortin Ligands in Disease Cachexia

恶病质中的黑皮质素配体

• 批准号: 8391683
• 负责人: Kenneth Allen Gruber
• 金额: $ 89.69万
• 依托单位: TENSIVE CONTROLS, INC.
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-15 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8391683
• 关键词: Acute; Adverse effects; Agonist; Amino Acids; Animal Cancer Model; Animal Disease Models; Animal Model; Anorexia; Apoptosis; Behavioral; Biological Assay; Blood - brain barrier anatomy; C-terminal; Cachexia; Cancer Model; Canis familiaris; Cardiac; Cardiovascular system; Cessation of life; Chronic; Clinical; Communicable Diseases; Complication; Cyclic Peptides; Data; Desire for food; Development; Disease; Dissociation; Dose-Limiting; Drug Kinetics; Eating; Electrocardiogram; Energy Intake; Epithelial; Etiology; Experimental Models; Food Energy; Food Intake Regulation; Goals; Grant; Heart Arrest; Heart Diseases; Heart Rate; Homeostasis; Human; Hybrids; Hyperactive behavior; Inflammatory; Investigation; Lead; Life; Ligands; Malignant Neoplasms; Measures; Mediating; Melanocortin 4 Receptor; Metabolic; Metabolic Control; Modeling; Movement; National Cancer Institute; Oral; Organ failure; Outcome; Peptides; Pharmaceutical Preparations; Pharmacodynamics; Phase; Play; Production; Property; RFamide peptide; Relative (related person); Reporting; Role; Sick Sinus Syndrome; Small Business Innovation Research Grant; Solutions; Symptoms; Syndrome; System; Therapeutic; Therapeutic Agents; Therapeutic Index; Treatment Efficacy; Work; absorption; arginylphenylalaninamide; cancer radiation therapy; cancer therapy; candidate selection; design; drug candidate; economic cost; hypocretin; in vivo; melanocortin receptor; pharmacophore; pre-clinical; preclinical study; pressure; research study

DESCRIPTION (provided by applicant): Cachexia-anorexia syndrome is a life-threatening aspect to many diseases, in particular many forms of cancer or therapies for cancer. The obvious symptoms of this disease include lack of appetite, and a loss of lean body mass disproportionate to the reduction in caloric intake. However, the less obvious effects include multi-organ failure, due to high metabolic rate-induced apoptosis. The economic costs of cachexia are huge. The National Cancer Institute estimates that up to 40% of cancer deaths are directly due to cachexia, and it is likely a factor in a significant percent of other cancer fataliies. Hyperactivity of the central melanocortin (MC) system appears to be a common factor in most, if not all, forms of cachexia. In addition, recent evidence indicates that the lethargy (lack of activity/movement) associated with cachexia inducing diseases is not MC system mediated, but rather due to suppression to the central orexin system. Thus, the ideal anti-cachectic drug would combine the properties of a MC antagonist and orexin system agonist or stimulator. Analysis of MCR ligands with in vivo assays, demonstrated the dissociation of MC from cardiovascular (C-V) activity, suggesting a solution to the long-standing problem of MC C-V side-effects Our Phase 1 "Proof of Concept" was to produce derivatives of MC peptide antagonists that chronically suppressed C-V activity, while maintaining anti-anorexic activity. Phase 1 of this project was highly successful. We first made a detailed investigation of MC C-V actions, using arterial pressure, heart rate, and the electrocardiogram. MC ligand C-V activities replicate actions associated with RFamide peptides in different experimental models. The direct cardiac effects modeled the clinical symptoms of "sick sinus syndrome" and "sudden cardiac arrest." Thus, the endogenous RFamide system may have an etiological role in these human cardiac disorders. We then designed and synthesized MC cyclic peptide antagonists with an enzymatically stable C-terminal extension. This compound had no C-V activity, lacked the dose-limiting behavioral side-effects associated with other anti-cachectic MC antagonists, produced a 100% reversal of cachexia in an aggressive experimental cancer model, and suppressed cachexia-induced lethargy. Our Phase 2 Specific Aims are 1) design a MC antagonist peptide to maximize oral absorption and blood brain barrier transport; 2) determine therapeutic index and pharmacokinetics in experimental models, and 3) confirm the anti-cachexia-anorexia effects in canine malignancies. Tensive Controls will complete the work necessary to develop anti-cachexia therapeutic, and move it into formal pre-clinical development. This will produce an anti-cachexia drug that will increase the treatment window for malignancies. PUBLIC HEALTH RELEVANCE: Melanocortins (MCs) are naturally substances that have potential use as therapeutic agents in cachexia, a condition of reduced appetite with enhanced metabolic rate. However, MCs have unacceptable cardiovascular effects. We propose to develop MC drugs with reduced side-effects.

描述（由申请人提供）：卡赫西亚 - 动物疾病综合征是许多疾病的威胁生命方面，尤其是许多形式的癌症或癌症疗法。这种疾病的明显症状包括缺乏食欲，而瘦体重的损失与摄入量的减少不成比例。然而，由于高代谢率诱导的凋亡而导致的较不明显的影响包括多器官失败。卡希克西亚的经济成本很大。国家癌症研究所估计，高达40％的癌症死亡直接是由于恶病质引起的，这可能是其他癌症死亡人数中很大一部分的因素。在大多数（如果不是全部）的卡氏症形式中，中央黑色皮质素（MC）系统的多动症似乎是一个常见因素。此外，最近的证据表明，与诱发恶病症相关的嗜睡（缺乏活性/运动）不是MC系统介导的，而是由于抑制了中枢Orexin System。因此，理想的抗促药物将结合MC拮抗剂和Orexin System激动剂或刺激剂的特性。 Analysis of MCR ligands with in vivo assays, demonstrated the dissociation of MC from cardiovascular (C-V) activity, suggesting a solution to the long-standing problem of MC C-V side-effects Our Phase 1 "Proof of Concept" was to produce derivatives of MC peptide antagonists that chronically suppressed C-V activity, while maintaining anti-anorexic activity.该项目的第一阶段非常成功。 我们首先使用动脉压，心率和心电图对MC C-V动作进行了详细研究。 MC配体C-V活性在不同的实验模型中复制与RFAMIDE肽相关的作用。直接的心脏作用模拟了“病态窦综合征”和“猝死心脏骤停”的临床症状。因此，内源性rfamide系统可能在这些人类心脏病中具有病因。 然后，我们设计并合成具有酶稳定的C末端延伸的MC环状肽拮抗剂。该化合物没有C-V活性，缺乏与其他抗抗癌MC拮抗剂相关的剂量限制行为副作用，在侵略性的实验性癌症模型中产生了100％的卡氏症，并抑制了卡希克西氏症诱导的嗜睡。 我们的第2阶段的特定目的是1）设计MC拮抗剂肽以最大程度地吸收口服吸收和血脑屏障的转运； 2）确定实验模型中的治疗指数和药代动力学，3）确认犬恶性肿瘤中的抗乙酰疾病 - 抗抗病作用。 紧张的控制将完成开发抗血清治疗的必要工作，并将其转化为正式的临床前发育。这将产生一种抗acachexia药物，以增加恶性肿瘤的治疗窗口。 公共卫生相关性：黑色素皮质蛋白（MCS）是天然物质，在卡氏症中可能用作治疗剂，这是一种食欲降低，代谢率提高。但是，MC具有不可接受的心血管效应。我们建议开发副作用降低的MC药物。