Investigation of the Potential Anti-Diabetic Activity of ITX2158 In Vivo

ITX2158 体内潜在抗糖尿病活性的研究

• 批准号: 7608527
• 负责人: Flossie Wong-Staal
• 金额: $ 15.32万
• 依托单位: ITHERX PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-10 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7608527
• 关键词: 2,4-thiazolidinedione; Adipocytes; Adverse effects; Affect; Agonist; Animal Model; Animals; Antidiabetic Drugs; Behavior; Biological Assay; Biological Factors; Body Weight; Body Weight decreased; Cardiovascular system; Chronic; Clinical; Clinical Chemistry; Data; Developed Countries; Developing Countries; Development; Diabetes Mellitus; Diabetic mouse; Dose; Drug Kinetics; Evaluation; Funding; Glucose; Health; Heart failure; Hormones; Human; In Vitro; Insulin; Insulin Resistance; Investigation; Lead; Leptin; Libraries; Liquid substance; Marketing; Maximum Tolerated Dose; Metabolic; Metabolic syndrome; Modeling; Monitor; Mus; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Oral; Outcome; Peroxisome Proliferator-Activated Receptors; Pharmaceutical Preparations; Pharmacology; Plasma; Population; Principal Investigator; Production; Property; Rattus; Research; Route; Schedule; Screening procedure; Societies; Testing; Therapeutic; Thiazolidinediones; Toxicology; Triglycerides; Weight Gain; adiponectin; analog; base; db/db mouse; design; diabetic; diabetic patient; diabetic rat; dosage; fasting blood glucose level; glucose tolerance; improved; in vivo; insulin sensitivity; insulin sensitizing drugs; intravenous administration; lipid biosynthesis; mouse model; novel; pre-clinical; programs; public health relevance; rosiglitazone; small molecule; treatment effect

DESCRIPTION (provided by applicant): Adiponectin is an anti-diabetic hormone exclusively secreted by adipocytes. Circulating adiponectin levels have been found to be low among obese and type II diabetic patients as compared to the normal population. Animal models and human studies suggest that elevated adiponectin levels increase insulin sensitivity. Weight loss or thiazolidinediones (TZDs) treatment increases plasma adiponectin levels. We have screened a library of drug-like compounds and natural products for novel agents that can enhance adiponectin production. We identified ITX2545 and its synthetic analogs as up-regulators of adiponectin secretion in vitro with potency levels comparable to that of rosiglitazone, a currently marketed anti-type II diabetic drug. However, unlike rosiglitazone, which acts as a PPAR agonist with weight gaining and cardiovascular side effects, ITX2545 and its analogs do not act on PPAR activity. These data suggest that ITX2545 and its analogs are potential anti-diabetic agents with novel mechanisms of action. The objective of this proposal is to investigate the pharmacology of the anti-diabetic activity of an optimal ITX2545-analog in vivo. The Specific Aims of the study are : (1) Preliminary PK-Tox evaluation - The best compounds will be selected based on in vitro potency and metabolic stability assays. Systemic exposure of the compounds will be assessed by LC-MS after oral or intravenous administration of the compounds. The delivery route that provides sufficient compound exposure in murine plasma will be used later for the efficacy study. The safe dose range will be determined by monitoring body weight, behavior, and clinical chemistry of the animals after compound administration and the results will guide the dosage for the efficacy study. (2) the in vivo efficacy study will be performed using ZDF diabetic rat model and db/db diabetic mouse model. Plasma level of adiponectin, glucose, insulin, leptin, FFA, triglyceride, and body weights will be used as the end points of anti-diabetic efficacy. A positive outcome of this in vivo efficacy study would provide the proof of principle for the anti-diabetic activity of the compound, and warrants its further development as an insulin sensitizer without the undesirable side effect associated with the current TDZs drugs on the market. PUBLIC HEALTH RELEVANCE: Animal studies revealed that elevated adiponectin levels alleviate metabolic syndrome. We identified small molecules that up-regulate adiponectin in vitro, and we hypothesize that these agents could be pharmacologically active in up-regulating adiponectin in vivo, thus potentially having therapeutic benefit against diabetes. The positive outcomes of the proposed studies may lead to the discovery of a novel class of agents for the treatment of metabolic syndrome.

性状（由申请方提供）：脂联素是一种仅由脂肪细胞分泌的抗糖尿病激素。与正常人群相比，肥胖和II型糖尿病患者的循环脂联素水平较低。动物模型和人体研究表明，脂联素水平升高会增加胰岛素敏感性。体重减轻或噻唑烷二酮（TZDs）治疗增加血浆脂联素水平。我们已经筛选了一个库的药物样化合物和天然产物的新的代理商，可以提高脂联素的生产。我们鉴定了ITX 2545及其合成类似物作为脂联素分泌的体外上调剂，其效力水平与目前市售的抗II型糖尿病药物罗格列酮相当。然而，与作为具有体重增加和心血管副作用的PPAR激动剂的罗格列酮不同，ITX 2545及其类似物不作用于PPAR活性。这些数据表明，ITX 2545及其类似物是具有新作用机制的潜在抗糖尿病药物。本提案的目的是研究最佳ITX 2545类似物体内抗糖尿病活性的药理学。本研究的具体目的是：（1）初步PK-毒性评价-将根据体外效价和代谢稳定性试验选择最佳化合物。在口服或静脉内给予化合物后，将通过LC-MS评估化合物的全身暴露。在小鼠血浆中提供足够化合物暴露的给药途径将在随后用于疗效研究。将通过监测化合物给药后动物的体重、行为和临床化学来确定安全剂量范围，结果将指导疗效研究的剂量。(2)使用ZDF糖尿病大鼠模型和db/db糖尿病小鼠模型进行体内功效研究。脂联素、葡萄糖、胰岛素、瘦素、FFA、甘油三酯和体重的血浆水平将用作抗糖尿病疗效的终点。该体内功效研究的积极结果将为该化合物的抗糖尿病活性提供原理证明，并保证其作为胰岛素增敏剂的进一步开发，而没有与目前市场上的TDZ药物相关的不良副作用。公共卫生相关性：动物研究表明，脂联素水平升高可缓解代谢综合征。我们鉴定了在体外上调脂联素的小分子，并且我们假设这些药物在体内上调脂联素时可能具有抑制活性，因此可能对糖尿病具有治疗益处。拟议研究的积极结果可能会导致发现一类治疗代谢综合征的新型药物。