Selective inhibitors of ubiquitin E3 ligase to treat high cholesterol

描述(申请人提供)：高胆固醇血症是心血管疾病的一个主要风险因素；据估计，美国有3500万人(或成年人口的六分之一)总胆固醇偏高，因此患心脏病的风险是那些具有最佳胆固醇水平的人的两倍。虽然他汀类药物被广泛用于降低胆固醇，但其严重的副作用使风险/收益考虑成为医生决定开出它们的重要因素。此外，单药他汀类药物 易发生耐药性的患者。因此，需要在治疗机制上与他汀类药物不同的新药；这种药物单独使用可能比他汀类药物引起的副作用更少，但更重要的是，它们可以与现有的药物联合使用，以防止耐药性的容易发展。几乎所有的降胆固醇药物都针对增加低密度脂蛋白受体(LDLR)的活性，该受体主要负责清除血清中的胆固醇；这一生理终点可以通过一些不同的生化机制实现。Progenra的第一阶段治疗假说提出通过最大限度地利用泛素-蛋白酶体途径来增加LDLR的活性，这是药物发现的一个新领域。既定的治疗靶点IDOL是一种环指E3-泛素连接酶，它能将泛素与其胞浆结构域上的LDLR结合，导致其随后的降解；该连接酶的抑制剂将有效地提高LDLR的平均水平。药理学结果是降低血清胆固醇水平，上调低密度脂蛋白受体是降低胆固醇的既定方法。事实上，最近的一项研究表明，在小鼠偶像基因敲除模型中，LDLR增加。Idol抑制剂将通过一种全新的机制完成这一治疗步骤。此外，选择性的Idol抑制剂可能会产生最小的副作用。因此，在第一阶段，建立并验证了IDOL抑制剂的高通量筛选试验，并对一组小分子进行了筛选。在这个屏幕上获得了几个合适的点击率。在第二阶段，建议对效力和选择性得到验证的HITS进行化学优化，并利用(1)生化和基于细胞的二次分析；(2)药物代谢/药代动力学特性和低密度脂蛋白清除(功效)的动物模型，启动选定的优化类似物的临床前开发。第二阶段的目的是确定有效和选择性的化合物作为降胆固醇的治疗剂。

DESCRIPTION (provided by applicant): Hypercholesterolemia is a major risk factor in cardiovascular diseases; it is estimated that >35 million individuals in the U.S. (or one-sixth of the adult population) have high total cholesterol and thus twice the risk of heart disease compared to those with optimal cholesterol levels. While statins are widely prescribed for cholesterol lowering, their serious side effect profile makes the risk/benefit consideration an important factor in a physician's decision to prescribe them. In addition, single agent statins are susceptible to the development of resistance in patients. Thus a need exists for new drugs that differ from statins in their therapeutic mechanisms; such drugs used singly have the potential to cause fewer side effects than statins but, more important, they could be used in combination with existing agents to prevent facile development of resistance. Nearly all cholesterol lowering drugs are directed at increasing the activity of the LDL Receptor (LDLR), which is primarily responsible for clearing cholesterol from the serum; this physiological endpoint can be achieved through a number of biochemically distinct mechanisms. Progenra's Phase I therapeutic hypothesis proposed to increase LDLR activity by maximizing its population utilizing the ubiquitin-proteasome pathway, a novel area for drug discovery. The posited therapeutic target, Idol, is a RING finger E3-ubiquitin ligase that conjugates ubiquitin to the LDLR on its cytoplasmic domain, resulting in its subsequent degradation; inhibitors of this ligase would effectively increase the average levels of LDLR. The pharmacologic outcome would be a reduction is the serum cholesterol level, and LDLR up-regulation is an established approach for cholesterol lowering. In fact, a recent study demonstrated increased LDLR in mouse Idol-knockout models. An Idol inhibitor would accomplish this therapeutic step by a completely novel mechanism. In addition, a selective inhibitor of Idol would be likely to produce minimal side effects. In Phase I, therefore, a high throughput screening assay for inhibitors of Idol was established and validated, and a screen was conducted on a set of small molecules. Several suitable hits were obtained in this screen. In Phase II it is proposed to perform chemical optimization on hits validated for potency and selectivity and initiate preclinical development of selected optimized analogues using (1) biochemical and cell-based secondary assays; and (2) animal models of drug metabolism/pharmacokinetic properties and LDL clearance (efficacy). The purpose of Phase II is to identify potent and selective compounds with efficacy as cholesterol-lowering therapeutic agents.