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

描述(申请人提供)：脂联素是一种由脂肪细胞独有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。减肥或噻唑烷二酮(TZDS)治疗会增加血浆脂联素水平。我们已经筛选了一系列类似药物的化合物和天然产物，以寻找可以促进脂联素生产的新型药物。我们确定ITX2545及其合成类似物在体外是脂联素分泌的上调调节剂，其效力水平与罗格列酮相当，罗格列酮是目前上市的抗II型糖尿病药物。然而，与罗格列酮不同，罗格列酮作为PPAR激动剂，具有体重增加和心血管副作用，ITX2545及其类似物不作用于PPAR活性。这些数据表明，ITX2545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优化的ITX2545类似物在体内的抗糖尿病活性的药理学。本研究的具体目的是：(1)初步的PK-Tox评价-将根据体外效力和代谢稳定性分析选出最好的化合物。口服或静脉注射化合物后，将通过LC-MS对化合物的全身暴露进行评估。在小鼠血浆中提供足够化合物暴露的递送路线将在稍后用于疗效研究。安全剂量范围将通过监测复合给药后动物的体重、行为和临床化学变化来确定，其结果将指导疗效研究的剂量。(2)采用ZDF糖尿病大鼠模型和db/db糖尿病小鼠模型进行体内药效研究。血浆脂联素、血糖、胰岛素、瘦素、游离脂肪酸、甘油三酯和体重水平将作为抗糖尿病疗效的终点。这项体内疗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，并保证其进一步开发为胰岛素增敏剂，而不会出现与目前市场上的TDZ药物相关的不良副作用。公共卫生相关性：动物研究表明，脂联素水平升高可以缓解代谢综合征。我们在体外发现了上调脂联素的小分子，并假设这些药物在体内可能具有上调脂联素的药理活性，从而潜在地对糖尿病有治疗作用。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药物。

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.