Liver Selective AMPK Activator to Treat Type 2 Diabetes

描述(申请人提供)：2型糖尿病(T2D)是一种毁灭性的疾病，在美国和世界各地的患病率都出现了惊人的增长。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，超过三分之一的受影响个人无法达到健康的血糖水平。在所使用的治疗方法中，以全世界开出的处方数量衡量，二甲双胍(即双胍类药物中的一种)是最突出的药物。然而，不幸的是，多达10%的潜在患者由于胃肠道不良反应而不能耐受这种药物，而另一组糖尿病患者，甚至更多的肾功能不全患者，由于乳酸酸中毒的风险而不能服用二甲双胍。乳酸酸中毒是一种威胁生命的疾病，由肾脏对二甲双胍的清除减少引起。在目前修订的申请中，提出了一项研究计划，以确定能够治疗无法服用二甲双胍或对该药物反应差的T2D受试者的新型双胍类药物。该计划基于OCT1和OCT2分别将双胍转运到肝和肾细胞。在这种方法中，将通过NovaTarg化学合成新的双胍类化合物，以增加它们对OCT1的亲和力，同时降低它们对OCT2的亲和力。我们期待通过增加肝脏(OCT1)的摄取来提高疗效，OCT1是双胍的靶组织。然而，通过肾脏(OCT2)消除二甲双胍的减少有望使药物暴露可预测，即使在肾功能受损的患者中也是如此。因此，通过改变消除模式，新的双胍类药物将有可能被肾功能不全的T2D受试者使用。最近发现，第三个OCT，即10月3日，可以将二甲双胍转移到骨骼肌中，这扩大了这项工作的范围。在这项修订后的应用中，将在10月3日测试新型双胍类化合物的活性和激活肌肉AMPK的能力。虽然肝脏仍然是我们主要关注的疗效，但对肝脏和肌肉都有作用的化合物应该会加强T2D患者的血糖控制。正如我们在初步数据中指出的那样，已经制定了一项化学计划，该计划表明，与二甲双胍相比，它有能力生成OCT1比OCT2选择性更高的双胍类化合物。重要的是，在初步结果中，某些新的双胍类化合物已经显示出能够激活肝脏和肌肉细胞中的AMPK，减少肝脏细胞的葡萄糖输出，并通过OGTT来加速小鼠体内的葡萄糖处置(见NT1014的数据)。这些令人鼓舞的结果表明，在一种40多年来没有经历过任何重大创新的药物类别中，成功的结果(即在有效性和安全性方面明显改善的二甲双胍)。

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.