Development of Small-Molecule HIV Entry Inhibitors

描述（由申请人提供）：迫切需要新的艾滋病毒治疗模式。目前HIV感染的治疗靶向病毒酶蛋白酶和逆转录酶。然而，这些疗法通常由于多药耐药变体的传播和出现而无法长期控制HIV，此外，这些治疗通常与不可忍受的副作用相关，因此大多数HIV感染者最终用尽了他们的治疗选择。 HIV进入为新一代抗病毒药物提供了一个有希望的靶点，最近的临床试验已经验证了进入作为一个可行的治疗靶点。然而，没有口服的HIV进入抑制剂进入高级临床试验。 在I期项目中，我们使用一种新的无病毒检测方法对400万种药物样组合化合物进行了超高通量筛选，该方法准确模拟了HIV进入的所有阶段，发现了几种活性化合物，最有希望的化合物被证明是一种无毒且特异性的HIV抑制剂，作用于膜融合水平，这种新型化合物来自一个有前途的铅系列，具有药物样性质，简单的化学和有前途的结构-活性关系。 该II期项目的总体目标是将先导系列开发成高度优化的化合物，以满足作为新的HIV疗法的人类临床测试的所有标准。协作药物优化计划结合了药典公司的医学和计算化学专业知识。与Progenics制药公司和我们在阿尔伯特爱因斯坦医学院的科学合作者的抗病毒和药物开发专业知识。该项目将采用一个综合和迭代的合成和生物测试过程，对1000多种化合物进行逐步优化，以获得抗病毒效力，选择性和药物相似性。进一步的研究确立了HIV对该化合物易感性的分子决定因素。最后，将在动物中测试最高度优化的化合物的口服药理学和耐受性，以确定最有必要进入人体临床试验的药物。 第二阶段项目的成功被定义为开发一种新型的、口服的、耐受性良好的化合物，该化合物以纳摩尔的效力广泛抑制HIV进入。项目的成功将导致临床级材料和监管文件的准备，将支持这种新的艾滋病毒疗法的人体临床试验。

DESCRIPTION (provided by applicant): There is an urgent need for new modes of HIV therapy. Current therapies for HIV infection target the viral enzymes protease and reverse transcriptase. However, these therapies typically fail to control HIV long-term due to the transmission and emergence of multidrug-resistant variants, In addition, these treatments are associated with often intolerable side effects, and thus most HIV-infected individuals eventually exhaust their therapeutic options. HIV entry provides a promising target for a new generation of antiviral agents, and recent clinical trials have validated entry as a viable target for therapy. However, no orally available HIV entry inhibitor has entered advanced clinical testing. In the Phase I project, we performed ultra-high throughput screening of 4 million drug-like combinatorial compounds using a novel virus-free assay that accurately models all stages of HIV entry, Several active compounds were discovered, and the most promising compound was demonstrated to be a nontoxic and specific HIV inhibitor that acts at the level of membrane fusion, This novel compound derives from a promising lead series that possesses drug-like properties, facile chemistry and promising structure-activity relationships. The overall goal of this Phase II project is develop the lead series into a highly optimized compound that meets all criteria for human clinical testing as a new HIV therapy. The collaborative drug optimization program combines the medicinal and computational chemistry expertise of Pharmacopeia, Inc. with the antiviral and drug development expertise of Progenics Pharmaceuticals and our scientific collaborators at Albert Einstein College of Medicine. The project will employ an integrated and iterative process of synthesis and biological testing of more than 1000 compounds that are progressively optimized for antiviral potency, selectivity and drug-likeness. Additional studies wit1 establish the molecular determinants of HIV susceptibility to the compound. Lastly, the most highly optimized compounds will be tested for oral pharmacology and tolerability in animals in order to identify the agent that most warrants advancement into human clinical testing. Success in the Phase II project is defined as the development of a novel, orally available and well-tolerated compound that broadly inhibits HIV entry with nanomolar potency. Project success would lead to the preparation of clinical-grade material and regulatory documentation that would support human clinical testing of this new HIV therapy.