Liver Selective AMPK Activator to Treat Type 2 Diabetes

肝脏选择性 AMPK 激活剂治疗 2 型糖尿病

• 批准号: 8589983
• 负责人: Ken W Batchelor
• 金额: $ 31.63万
• 依托单位: NOVATARG, 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 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8589983
• 关键词: 5' -AMP-activated protein kinase; Adult; Adverse effects; Affect; Affinity; Animal Model; Animals; Antidiabetic Drugs; Biguanides; Biological Assay; Blood; Blood Glucose; Caring; Cells; Characteristics; Chemistry; Data; Development; Diabetes Mellitus; Disease; Dose; Drug Exposure; Drug Prescriptions; Effectiveness; Employee Strikes; Ensure; Europe; Evaluation; Excretory function; Expenditure; Gastrointestinal tract structure; Goals; Healthcare; Hepatic; Hepatocyte; Hormones; Human; Impaired Renal Function; In Vitro; Individual; Kidney; Kidney Failure; Lactic Acidosis; Lactic acid; Life; Liver; Measures; Medicine; Metabolism; Metformin; Molecular; Mus; Muscle; Muscle Cells; New Agents; Non-Insulin-Dependent Diabetes Mellitus; OGTT; Outcome; POU2F1 gene; POU2F2 gene; Patients; Pattern; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacology; Phase; Phenformin; Population; Preclinical Testing; Prevalence; Property; Research; Risk; Safety; Skeletal Muscle; Testing; Therapeutic; Tissues; Translating; Work; base; cell motility; design; diabetes mellitus therapy; diabetic; diabetic patient; drug candidate; experience; gastrointestinal; glucagon-like peptide 1; glucophage; glucose disposal; glucose metabolism; glucose output; hepatic gluconeogenesis; improved; in vitro Assay; in vivo; innovation; kidney cell; member; novel; novel strategies; phase 1 study; programs; public health relevance; research clinical testing; response; uptake

DESCRIPTION (provided by applicant): Type 2 diabetes (T2D) is a devastating disease that has undergone a striking increase in prevalence in the U.S. and worldwide. Although a number of different drugs exist to help manage this condition, unfortunately more than 1/3 of affected individuals fail to achieve healthy blood glucose levels. Of the therapies used, metformin (i.e. Glucophage, a member of the biguanide drug class) is the most prominent of the drugs as measured by the number of prescriptions issued worldwide. Unfortunately however, up to 10% of potential patients cannot tolerate this agent because of gastrointestinal adverse effects while another, even larger, segment of the diabetic population with renal insufficiency cannot take metformin because of the risk of lactic acidosis, a life-threatening condition caused by a decrease in metformin elimination by the kidney. In the current revised application, a research plan is proposed to identify novel biguanides that can treat the segment of T2D subjects who are unable to take metformin or respond poorly to this drug. The plan is based on the transport of biguanides into liver and kidney cells by OCT1 and OCT2, respectively. In this approach, new biguanides will be synthesized by NovaTarg chemistry to increase their affinity for OCT1 while reducing their affinity for OCT2. We anticipate an increase in efficacy from the increase in uptake by the liver (OCT1), the target tissue of biguanides. Whereas a decrease in metformin elimination via the kidney (OCT2) is expected to make drug exposure predictable even in patients with impaired renal function. Thus, by changing the elimination pattern, the new biguanides will have the potential to be used by T2D subjects with renal insufficiency. The recent discovery that a third OCT, OCT3, acts to transport metformin into skeletal muscle has enlarged the scope of this work. In this revised application the novel biguanides will be tested for their activity on OCT3 and their ability to activate muscle AMPK. Although liver remains our primary focus on efficacy, compounds that can act on both liver and muscle should augment the control of blood glucose in T2D patients. As pointed out in our preliminary data, a chemistry plan is in place that has shown its ability to generate biguanides with improved selectivity for OCT1 over OCT2 when compared to metformin. Importantly in preliminary results, certain of these new biguanides have demonstrated an ability to activate AMPK in liver and muscle cells, to reduce hepatic cell glucose output, and to accelerate glucose disposal in mice as measure by an OGTT (see data for NT1014). These encouraging results argue for a successful outcome (i.e. a markedly improved metformin, both in efficacy and safety) in a drug class that has not experienced any significant innovation in over 40 years.

描述（由申请人提供）：2型糖尿病（T2D）是一种毁灭性的疾病，在美国和全球的患病率显着提高。尽管存在许多不同的药物来帮助管理这种情况，但不幸的是，超过1/3的患者无法达到健康的血糖水平。在使用的疗法中，二甲双胍（即Glucophage，Biguanide药物类的成员）是由全球发布的处方数量来衡量的最突出的药物。但是，不幸的是，高达10％的潜在患者由于胃肠道不良反应无法忍受这种药物，而另一个肾脏不足的糖尿病人群中，由于乳酸酸中毒的风险，肾脏不足的糖尿病人群无法患有二甲双胍，这是由于肾脏消除二甲双胍的降低而导致生命的疾病。在当前的修订应用中，提出了一项研究计划，以识别可以治疗无法服用二甲双胍或对这种药物反应不佳的T2D受试者细分市场的新型Biguanides。该计划分别基于Biguanides到OCT1和OCT2的运输到肝脏和肾细胞。在这种方法中，Novatarg Chemistry将合成新的Biguanides，以提高其对OCT1的亲和力，同时降低其对OCT2的亲和力。我们预计，肝脏（OCT1）（Biguanides的靶组织）摄取的摄取增加会增加。而通过肾脏消除二甲双胍的减少（OCT2）也有望使药物暴露也可以预见，即使在肾功能受损的患者中也可以预测。因此，通过更改消除模式，新的Biguanides有可能被肾脏功能不全的T2D受试者使用。最近的发现，即10月3日，将二甲双胍转移到骨骼肌中的发现扩大了这项工作的范围。在此修订的应用中，新型Biguanides将在OCT3上的活性以及激活肌肉AMPK的能力进行测试。尽管肝脏仍然是我们对疗效的主要关注，但是可以对肝脏和肌肉起作用的化合物应增加T2D患者血糖的控制。正如我们的初步数据中所指出的那样，与二甲双胍相比，OCT1超过OCT1的选择性提高了Biguanides的能力，该化学计划已经显示出其能力。重要的是，在初步结果中，这些新的Biguanides中的某些表现出激活肝脏和肌肉细胞中AMPK，减少肝细胞葡萄糖输出的能力，并通过OGTT作为度量中加速小鼠中的葡萄糖处置（请参阅NT1014的数据）。这些令人鼓舞的结果表明，在40多年来从未经历过任何重大创新的药物类别中，成功的结果（即在疗效和安全性方面明显改善的二甲双胍）。