双重靶向CYP11B2及盐皮质激素受体用以治疗充血性心衰

To prevent the deleterious effects of excessive aldosterone in inducing congestive heart failure, it was proposed innovatively to inhibit the biosynthesis of aldosterone and to block the downstream signal transduction simultaneously via dual-targeting CYP11B2 and mineralocorticoid receptor (MR) in order to treat congestive heart failure in synergism and avoid drug resistance caused by accumulation of aldosterone and up-regulation of corticosterone. In a preliminary experiment in rats with heart failure, more improvement of heart functions was observed for the combinatory application of MR antagonist Eplerenone and CYP11B2 inhibitor HQZ95 compared to solo applications of each compound. In the proposed project, this innovative strategy will be further explored by designing and synthesizing selective aldosterone inhibitor simultaneously antagonizing MR via rational design of multi-targeting agents based on comparison of target crystal structures and pharmacophore models. Such dual-targeting compounds are expected to show anticipated efficacy, but to avoid potential off-target effects and drug-drug interactions. The mechanism and efficacy of these compounds on treatment of heart failure and avoidance of resistance will also be studied in animal models. This project is promising in afford new drugs with novel mechanisms in treating heart failure, and, more importantly, a validation of therapeutic concept that blockage of both biosynthesis and downstream signal transduction is superior, which could be applied to other treatment areas.

为彻底阻断过量的醛固酮导致充血性心衰的病理作用，我们创新性地提出双重靶向CYP11B2及盐皮质激素受体（MR），来同时抑制醛固酮的生物合成并拮抗其下游信号传导，以期协同治疗充血性心衰并避免因醛固酮蓄积或皮质甾酮上调而产生的耐药。在大鼠心衰模型预试验中，联合应用MR拮抗剂依普利酮和CYP11B2抑制剂HQZ95显示出较其分别单独应用更强的心脏保护作用。本项目拟进一步验证以上科学假说，通过开拓结合晶体结构对比和药效团模型的多靶点药物设计手段，来设计与合成能实现联合用药功效的单分子双靶点化合物，以期降低与联合用药相关的潜在的脱靶效应和药物-药物相互作用的风险。并将在动物模型中深入探讨这些双靶点化合物治疗心衰和心肌纤维化以及避免耐药性产生的机制与功效。这一研究不但可以为治疗充血性心衰开发新作用机制的创新药物，而且能够验证同时阻断生物合成及下游信号传导的治疗策略，以使之有望推广到其他疾病治疗领域。

充血性心衰是一种具有高发病率、高死亡率并缺乏有效药物疗法的严重疾病。而过量醛固酮在充血性心衰的发生和发展过程中扮演着重要的角色。为彻底阻断过量的醛固酮导致充血性心衰的病理作用，我们创新性地提出双重靶向醛固酮合成酶（CYP11B2）及盐皮质激素受体（MR），来同时抑制醛固酮的生物合成并拮抗其下游信号传导，以期协同治疗充血性心衰并避免因醛固酮蓄积或皮质甾酮上调而产生的耐药。通过晶体结构对比和药效团模型的联合使用，我们设计了苯并[f][1,4]氧氮杂䓬-5(2H)-酮类、吡啶取代的甲撑苯并异恶唑类及六氢甲撑咔唑类三个系列化合物。其对于CYP11B2和MR双靶点均表现出较好的抑制活性，并对相应的同源酶11羟化酶及糖皮质激素受体显示出较好的选择性。由此为选择性单分子多靶点化合物的理性设计探索了创新策略，并对其有效性和实用性进行验证。代表性化合物5X在大鼠体内表现出良好的药代动力学性质，并在阿霉素诱导的慢性心衰大鼠模型中，对于血浆及心脏组织中醛固酮浓度的具有显著的降低作用，而对糖皮质激素的生物合成没有产生消极影响。通过心电图监测、检验B型脑钠肽和心肌羟脯氨酸的血浆水平以及测定血流动力学参数表明化合物5X对于慢性心衰有较好的治疗作用。该研究不但可以为治疗充血性心衰开发新作用机制的创新药物，而且探索了同时阻断内源性调控分子信号传导途径中的两个重要节点，也就是生物合成和受体结合，相对于单一调节的优越性，例如：阻断后门路径以改善治疗效果及避免耐药性等。为目前临床上使用的众多类似的单点治疗途径提供进一步优化的线索，有望推广到其他疾病治疗领域。

内容获取失败，请点击重试