Adiponectin Secretion Enhancer Synthetic Organic Drug Discovery and Development

脂联素分泌增强剂合成有机药物的发现和开发

• 批准号: 8832009
• 负责人: Deborah Mai
• 金额: $ 81.21万
• 依托单位: DISCOVERYBIOMED, INC.
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-15 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8832009
• 关键词: Adipocytes; Adipose tissue; Adoption; Alabama; Animal Model; Atherosclerosis; Attenuated; Award; Back; Belief; Biochemistry; Biological; Biological Assay; Biological Markers; Blood; Blood Glucose; Cardiovascular Diseases; Cells; Chemicals; Clinical; Collaborations; Collection; Communicable Diseases; Complex; Critical Pathways; Development; Diabetes Mellitus; Diabetic Nephropathy; Diabetic Retinopathy; Diet; Disease; Enhancers; Epidemic; Evaluation; Explosion; Eye; Eye Injuries; Fatty Liver; Fatty acid glycerol esters; Funding; Goals; Health Care Costs; Heart; Heart Diseases; Human; Human body; Hyperglycemia; In Vitro; Injectable; Injury; Insulin; Kidney; Kindling (Neurology); Lead; Licensing; Life Style; Ligands; Link; Liver; Liver diseases; Marketing; Maximum Tolerated Dose; Mediator of activation protein; Metabolic Diseases; Metabolism; Mission; Modeling; Molecular Weight; Morbidity - disease rate; Mus; National Institute of Diabetes and Digestive and Kidney Diseases; Nature; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Obesity associated disease; Oral Medicine; Organ; Output; Overweight; Peptides; Performance; Peripheral Nerves; Pharmaceutical Chemistry; Pharmaceutical Preparations; Phase; Preparation; Process; Production; Proteins; Rattus; Research; Safety; Series; Small Business Innovation Research Grant; Societies; Source; Stroke; Therapeutic; Tissues; Toxic effect; Visceral; Work; adiponectin; analog; attenuation; base; combat; cost; design; diabetic; drug candidate; drug development; drug discovery; glycosylation; high throughput screening; human tissue; improved; in vivo; injured; innovation; interest; novel; novel therapeutics; pre-clinical; programs; public health relevance; research and development; sedentary lifestyle; small molecule; subcutaneous; success; three dimensional structure; trend

 DESCRIPTION (provided by applicant): DiscoveryBioMed, Inc. (DBM) completed recently Phase I SBIR-funded goals, milestones, specific experimental aims and efforts to screen 58,000 synthetic organic small molecules on immortalized and primary differentiated human adipocyte platforms and to validate the high-throughput screening (HTS)-based Drug Discovery output with a Critical Path of bioassays detecting secretion of endogenously produced species of the peptide adipokine, adiponectin. This design yielded 12 hit-to-lead chemical classes that are potent and effective in potentiating the endogenous production and secretion of human low, medium and higher molecular weight (HMW) forms of adiponectin, a beneficial adipokine for normal metabolism and insulin target tissue protection that is lost during the emergence and progression of type 2 diabetes mellitus (T2DM) and obesity. Accordingly, up-regulating endogenous adiponectin expression and secretion within the human body has been proposed as a therapeutic strategy for diabetes and obesity, especially to block secondary injury of other fragile human tissues. The ultimate goal of this proposed Phase II work is to select, profile, focus and optimize through medicinal chemistry DBM's lead and back-up lead chemical classes of higher molecular weight adiponectin secretagogue ligands (HMW-ASLs) to realize potent and effective lead clinical candidate drugs that will block secondary complications of T2DM, obesity and related metabolic diseases in the nearer term and attenuate T2DM and obesity in general as a secondary endeavor. The key ingredient in this program is the use of biologically- and disease-relevant human cellular platforms, primary differentiated human adipocytes, to profile hit-to-lead new chemical entities. This core principle reflects DBM's unique angle, approach and offering to the Drug Discovery space, 'Humanized Drug Discovery'. It is DBM's core belief that a successful de novo drug discovery program must utilize a disease-relevant human cell platform and a disease-relevant targeted and phenotypic endpoint (i.e. human adipocytes secreting human adiponectin). The rationale and potential market impact of this DBM Metabolic Diseases Drug Discovery and Development program are straightforward and enormous. Obesity and obesity-related diseases including T2DM, atherosclerosis, cardiovascular disease, fatty liver disease, and diabetic hyperglycemic injury of the eye, heart, vasculature, kidney and peripheral nerves have reached epidemic proportions in the US and the developed world and exact huge morbidity and cost burdens on global society. An immense unmet clinical need exists for new therapeutic drugs to combat these diseases, especially in Alabama where our company resides in the heart of "the Southeastern Diabetes Belt." This market is estimated to be $1 trillion by 2015. Yet, metabolic diseases drug discovery and development is at a near standstill. Hence, there is an 'open window of opportunity' to re-kindle the metabolic disease drug discovery effort. Our NIDDK Phase I SBIR award has allowed DBM to launch this critical program. Phase II project milestones are proposed as follows and will continue the momentum of this SBIR- driven program. Current transitional scientific activity seeks to evaluate and select multiple lead and back-up lead chemical series that are potent and effective HMW-ASLs at the onset of the program. Chemoinformatics analyses progressed 12 out of 18 validated hit chemical classes and subsequent medicinal chemistry analyses have selected 8 out of 12 hit-to-lead chemical classes for entry into Phase 2 SBIR-driven work. A continuing milestone seeks to profile 'best in class' compounds from the 8 hit-to-lead HMW-ASL classes in primary human adipocyte culture platforms from normal, T2DM, and overweight/obese donors and from both subcutaneous and visceral adipose tissue sources. Subsequent milestones involve collaborative work with CROs and academic collaborators/consultants in in vitro and in vivo ADME/PK and MTD safety and toxicity studies in mice, in vivo proof-of-concept studies in animal models of T2DM, obesity and related disorders, medicinal chemistry design optimization and profiling of analogs from, ultimately, 2 lead and 2 back-up lead drug classes to improve potency and/or efficacy of chemical series and re-performance of in vivo proof-of-concept studies in metabolic diseases animal models. This proposed Phase II program scripts full IND-enabling studies so as to select a lead clinical candidate drug and seek partnership with an interested BioPharma.

 描述（由申请人提供）：DiscoveryBioMed，Inc. (DBM)最近完成了SBIR资助的I期目标、里程碑、具体实验目标和努力，以在永生化和初级分化的人脂肪细胞平台上筛选58，000种合成有机小分子，并通过检测内源性产生的肽脂肪因子脂联素的分泌的生物测定的关键路径来验证基于高通量筛选（HTS）的药物发现输出。该设计产生了12种命中先导化合物类别，其在增强人低、中和高分子量（HMW）形式的脂联素的内源性产生和分泌方面是有效的和有效的，脂联素是一种有益于正常代谢和胰岛素靶组织保护的脂肪因子，其在2型糖尿病（T2 DM）和肥胖症的出现和进展期间丢失。因此，上调人体内内源性脂联素的表达和分泌已被提出作为糖尿病和肥胖症的治疗策略，特别是阻断其他脆弱人体组织的继发性损伤。这项拟议的第二阶段工作的最终目标是通过药物化学选择，概况，重点和优化DBM的铅和备份铅化学类的高分子量脂联素促分泌素配体（HMW-ASL）以实现阻断T2 DM继发性并发症的强效和有效的领先临床候选药物，肥胖症和相关代谢疾病，并作为次要的奋进减轻T2 DM和肥胖症。该计划的关键成分是使用生物学和疾病相关的人类细胞平台，原代分化的人类脂肪细胞，来分析命中导致的新化学实体。这一核心原则反映了DBM对药物发现领域“人性化药物发现”的独特视角、方法和产品。DBM的核心信念是，成功的从头药物发现计划必须利用疾病相关的人类细胞平台和疾病相关的靶向和表型终点（即分泌人脂联素的人脂肪细胞）。这个DBM代谢疾病药物发现和开发计划的基本原理和潜在的市场影响是直接和巨大的。肥胖和肥胖相关疾病，包括T2 DM、动脉粥样硬化、心血管疾病、脂肪肝疾病和糖尿病性高血糖对眼睛、心脏、血管系统、肾脏和外周神经的损伤，在美国和发达国家已达到流行病的程度，并给全球社会带来巨大的发病率和成本负担。一个巨大的未满足的临床需要存在新的治疗药物来对抗这些疾病，特别是在亚拉巴马，我们公司居住在“东南部糖尿病带的心脏。“到2015年，这个市场估计将达到1万亿美元。然而，代谢性疾病药物的发现和开发几乎处于停滞状态。因此，有一个“打开的机会之窗”来重新点燃代谢疾病药物发现的努力。我们的NIDDK第一阶段SBIR奖允许DBM推出这一关键计划。第二阶段项目里程碑建议如下，并将继续这一SBIR驱动的计划的势头。目前的过渡性科学活动旨在评估和选择多个铅和备份铅化学系列，这些化学系列在项目开始时是有效的和有效的HMW-ASL。化学信息学分析进展了18种经验证的命中化学类别中的12种，随后的药物化学分析选择了12种命中先导化学类别中的8种进入第2阶段SBIR驱动的工作。一个持续的里程碑旨在在正常、T2 DM和超重/肥胖供体以及皮下和内脏脂肪组织来源的原代人脂肪细胞培养平台中，对8种主要HMW-ASL类别中的“同类最佳”化合物进行分析。随后的里程碑包括与CRO和学术合作者/顾问在小鼠体外和体内ADME/PK和MTD安全性和毒性研究、T2 DM、肥胖和相关疾病动物模型的体内概念验证研究、药物化学设计优化和类似物分析方面的合作，最终，2种先导药物和2种备用先导药物类别，以提高化学系列的效力和/或疗效，并在代谢疾病动物模型中重新进行体内概念验证研究。这一拟议的II期计划将编写完整的IND使能研究，以选择一种领先的临床候选药物，并寻求与感兴趣的BioPharma的合作伙伴关系。