Selective inhibitors of ubiquitin E3 ligase to treat high cholesterol

描述（由申请人提供）：高胆固醇血症是心血管疾病的主要风险因素;据估计，美国有> 3500万人（或六分之一的成年人口）总胆固醇高，因此与具有最佳胆固醇水平的人相比，患心脏病的风险是其两倍。虽然他汀类药物被广泛用于降低胆固醇，但其严重的副作用特征使得风险/获益考虑成为医生决定开药的重要因素。此外，单药他汀类药物是 容易在患者中产生耐药性。因此，需要在其治疗机制上与他汀类药物不同的新药;单独使用这种药物具有比他汀类药物引起更少副作用的潜力，但更重要的是，它们可以与现有药物联合使用，以防止耐药性的轻易发展。几乎所有的降胆固醇药物都是针对增加LDL受体（LDLR）的活性，LDL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许多生物化学上不同的机制来实现。Progenra的I期治疗假说提出，通过利用泛素-蛋白酶体途径（药物发现的新领域）最大化LDLR群体来增加LDLR活性。假定的治疗靶点Idol是一种环指E3-泛素连接酶，其将泛素与其胞质结构域上的LDLR偶联，导致其随后降解;该连接酶的抑制剂将有效增加LDLR的平均水平。药理学结果将是血清胆固醇水平降低，LDLR上调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Idol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，选择性的偶像抑制剂可能会产生最小的副作用。因此，在I期，建立并验证了Idol抑制剂的高通量筛选测定，并对一组小分子进行筛选。在该筛选中获得了几个合适的命中。在II期研究中，建议对经效价和选择性验证的命中物进行化学优化，并使用（1）生物化学和基于细胞的二次试验;和（2）药物代谢/药代动力学特性和LDL清除（疗效）的动物模型启动选定优化类似物的临床前开发。II期的目的是鉴定具有降低胆固醇治疗剂功效的有效和选择性化合物。

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.