Development of Novel Small Molecule Therapies for Skeletal Muscle Atrophy

骨骼肌萎缩新型小分子疗法的开发

• 批准号: 8712083
• 负责人: Christopher M Adams
• 金额: $ 22.5万
• 依托单位: EMMYON, INC.
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-15 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8712083
• 关键词: Affect; Anabolism; Anterior Cruciate Ligament; Bed rest; Canis familiaris; Characteristics; Chemicals; Chemistry; Chronic Obstructive Airway Disease; Clinical; Clinical Research; Critical Illness; Development; Diabetes Mellitus; Disease; Dose; Drug Kinetics; Elderly; Evaluation; Exercise; FDA approved; Fracture; Goals; Government; Health; Heart failure; Hospitalization; Human; Hypertrophy; In Vitro; Injury; Intellectual Property; Iowa; Kidney Failure; Lead; Legal patent; Licensing; Malignant Neoplasms; Marketing; Mediation; Medical; Medicine; Methods; Mus; Muscle Cells; Muscle Fibers; Muscle function; Muscular Atrophy; Nursing Homes; Nutritional; Orthopedics; Patients; Persons; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Physical Rehabilitation; Plants; Prevention; Proteins; Quality of life; Rattus; Rehabilitation therapy; Relative (related person); Research; Safety; Secondary to; Series; Skeletal Muscle; Small Business Technology Transfer Research; Spinal cord injury; Staging; Stroke; Structure; Testing; Therapeutic; Tomatoes; Toxicology; Universities; Work; base; celecoxib; cell growth; commercialization; companion animal; design; drug discovery; falls; fluoromethyl 2,2-difluoro-1-(trifluoromethyl)vinyl ether; human data; human subject; improved; in vitro Model; inhibitor/antagonist; ligament injury; mRNA Expression; mortality; mouse model; muscle hypertrophy; muscle strength; novel; nutrition; phase 2 study; prevent; programs; public health relevance; quadriceps muscle; research and development; skeletal; small molecule

DESCRIPTION (provided by applicant): Skeletal muscle atrophy is a widespread and serious medical problem. Frequent causes of skeletal muscle atrophy include orthopedic injuries, bed rest, advanced age, cancer, heart failure, COPD, diabetes, stroke, renal failure, critical illness and spinal cord injury. Effects of skeletal muscle atrophy include weakness, reduced activity, falls, fractures, debilitation, prolonged hospitalization and rehabilitation, nursing home placement, and increased mortality. Although skeletal muscle atrophy has broad clinical impact, a pharmacologic therapy for muscle atrophy does not exist, and current therapeutic approaches (nutrition and physical rehabilitation) are often ineffective and/or unfeasible. Thus, skeletal muscle atrophy represents an enormous unmet medical need and market worldwide. The overall goal of Emmyon, Inc. is to develop a pharmacologic therapy for skeletal muscle atrophy. In preliminary studies, Emmyon's founders at the University of Iowa discovered a confidential and proprietary small molecule compound (compound A) that: 1) inhibits skeletal muscle atrophy, stimulates muscle hypertrophy, and increases strength and exercise capacity in mice; and 2) stimulates protein accretion and cellular hypertrophy in cultured skeletal myotubes from humans and mice. Based on this work, the University of Iowa applied for patents containing use claims for compound A in the prevention and treatment of skeletal muscle atrophy. Emmyon is in the final stages of negotiating an exclusive license to this intellectual property. From a commercialization standpoint, compound A is an attractive lead compound for pharmaceuticals that could prevent and treat muscle atrophy in humans and companion animals. However, composition-of-matter claims, which are critical for pharmaceutical development, are not possible. Thus, to develop a pharmaceutical for skeletal muscle atrophy, one of Emmyon's central R&D goals is to discover and develop potent and effective novel chemical entities (NCEs) whose structures are based on compound A. These NCEs will enable composition-of-matter claims, and may possess significantly improved pharmacologic characteristics relative to compound A. In this phase I STTR study, Emmyon will identify potent and effective compound A-based novel chemical entities (NCEs) with high commercial potential as pharmaceuticals. A series of patentable compound A-based NCEs will be synthesized and compared to compound A in human skeletal myotubes. NCEs with increased potency and/or efficacy relative to compound A will then be tested for their capacity to reduce skeletal muscle atrophy in mice. In Phase II studies, Emmyon will carry the most promising NCE forward into pharmacokinetic and toxicology studies in rats and dogs, and then an IND application. The initial clinical study would be geared towards FDA approval for the prevention and treatment of muscle atrophy in orthopedic patients. Subsequent studies would be geared towards FDA approval for other causes of skeletal muscle atrophy, which are also predicted to be amenable to these NCEs.

描述（由申请人提供）：骨骼肌萎缩是一种广泛而严重的医学问题。骨骼肌萎缩的常见原因包括骨科损伤、卧床休息、高龄、癌症、心力衰竭、COPD、糖尿病、中风、肾衰竭、危重病和脊髓损伤。骨骼肌萎缩的影响包括虚弱、活动减少、福尔斯、骨折、虚弱、住院和康复时间延长、疗养院安置和死亡率增加。虽然骨骼肌萎缩具有广泛的临床影响，但肌肉萎缩的药物治疗并不存在，并且目前的治疗方法（营养和物理康复）通常无效和/或不可行。因此，骨骼肌萎缩代表了世界范围内巨大的未满足的医疗需求和市场。Emmyon，Inc.的总体目标是开发一种骨骼肌萎缩的药物疗法。在初步研究中，Emmyon在爱荷华州大学的创始人发现了一种机密和专有的小分子化合物（化合物A）：1）抑制骨骼肌萎缩，刺激肌肉肥大，增加小鼠的力量和运动能力; 2）刺激人类和小鼠培养的骨骼肌管中的蛋白质增加和细胞肥大。基于这项工作，爱荷华州大学申请了含有化合物A在预防和治疗骨骼肌萎缩中的用途声明的专利。Emmyon正处于谈判该知识产权独家许可的最后阶段。从商业化的角度来看，化合物A是一种有吸引力的药物先导化合物，可以预防和治疗人类和伴侣动物的肌肉萎缩。然而，对于药物开发至关重要的物质组成声明是不可能的。因此，为了开发骨骼肌萎缩的药物，Emmyon的核心研发目标之一是发现和开发其结构基于化合物A的强效和有效的新型化学实体（NCE）。这些NCE将使物质组成声明成为可能，并且相对于化合物A可能具有显著改善的药理学特征。在这项I期STTR研究中，Emmyon将确定具有高商业潜力的基于化合物A的新型化学实体（NCE）。将合成一系列可获得专利的基于化合物A的NCE，并将其与人骨骼肌管中的化合物A进行比较。然后测试相对于化合物A具有增加的效力和/或功效的NCE减少小鼠骨骼肌萎缩的能力。在II期研究中，Emmyon将把最有前途的NCE推进到大鼠和狗的药代动力学和毒理学研究中，然后是IND申请。最初的临床研究将面向FDA批准预防和治疗骨科患者的肌肉萎缩。随后的研究将面向FDA批准骨骼肌萎缩的其他原因，预计这些原因也适用于这些NCE。