DESIGN AND SYNTHESIS OF NONPEPTIDE PROTEASE INHIBITORS

说明(申请人提供)：1996年将HIV-1蛋白酶抑制剂(PI)纳入两种或两种以上逆转录酶抑制剂的联合治疗方案，对于降低艾滋病相关死亡率、改善生活质量和加强艾滋病毒/艾滋病管理至关重要。高效抗逆转录病毒疗法(HAART)仍然是艾滋病毒/艾滋病最有效的治疗选择，但目前的治疗方案有许多严重的局限性。对多种药物产生抗药性的HIV-1变种的出现可能是最艰巨的挑战之一。在我们为开发新一代蛋白酶抑制剂而进行的持续合作研究中，我们的基于结构的设计策略导致了蛋白酶抑制剂UIC-94017(后来命名为TMC-114，或达鲁那韦)的设计和发现。达鲁那韦表现出显著的抗病毒活性，对多药耐药菌株具有良好的耐药性，并具有良好的药代动力学特性。2006年6月23日，达鲁那韦被FDA批准为治疗耐药艾滋病毒的首个药物。达鲁那韦是对抗抗药性艾滋病毒的新一代抑制剂中的第一种。然而，对于长期有效的治疗来说，它远不是理想的。关于口服生物利用度、药片负担和可能随着时间的推移出现耐药性的问题仍有待回答。基于我们的达鲁那韦结合的HIV蛋白酶的高分辨率X射线晶体结构和其他一些蛋白质配体结构，我们设想了一些有趣的设计概念和开发的工具来对抗耐药性。我们已经进行了初步的构效关系研究，并生成了一些小分子先导化合物。这项工作现在构成了我们拟议的研究的基础，这些研究包括：(A)基于结构设计和合成双-四氢呋喃和非磺酰胺类药物的新型PI；(B)设计和开发新型配体和支架以改善环戊基四氢呋喃(cp-THF)衍生的PI的药理学特性；(C)基于结构设计和开发新型模板、支架和杂环配体以生成新型小分子类药物PI；(D)深入抗药性研究和确定选定抑制剂的X射线结构以获得分子洞察力。本研究结合有机合成、蛋白质配基X-射线结晶学、分子模拟以及深入的病毒和细胞生物学研究，设计了下一代HIV-1蛋白酶抑制剂。

DESCRIPTION (provided by applicant): The incorporation of HIV-1 protease inhibitors (PIs) in 1996 into combination therapy regimens with two or more reverse transcriptase inhibitors has been critical to the reduction of AIDS related mortality, improvement of quality of life, and enhancement of HIV/AIDS management. Highly active antiretroviral therapy (HAART) remains the most effective treatment option for HIV/AIDS, but there are many serious limitations of current treatment regimens. The emergence of multidrug-resistant HIV-1 variants is perhaps, one of the most formidable challenges. In our continuing collaborative research efforts toward developing new generations of protease inhibitors, our structure-based design strategies have led to the design and discovery of protease inhibitor UIC-94017 (later named TMC-114, or darunavir). Darunavir has exhibited marked antiviral activity, excellent drug resistance profiles against multidrug-resistant strains and favorable pharmacokinetic properties. On June 23, 2006, darunavir was approved by the FDA as the first treatment for drug-resistant HIV. Darunavir represents the first of a new generation of inhibitors to combat drug-resistant HIV. However, it is far from ideal for long-term effective treatment. Issues concerning oral bioavailability, pill-burden and possible emergence of resistance over time remain to be answered. Based upon our high resolution X-ray crystal structures of darunavir-bound HIV protease and a number of other protein-ligand structures, we have envisioned a number of intriguing design concepts and developed tools to combat drug-resistance. We have carried out preliminary structure-activity studies and generated a number of small molecule leads. This work now forms the basis of our proposed studies which include: (a) structure-based design and synthesis of bis-THF-derived and nonsulfonamide-based novel drug-like PIs; (b) design and development of novel ligands and scaffolds to improve pharmacological profiles of cyclopentyl-tetrahydrofuran (cp-THF)-derived PIs; (c) structure-based design and development of novel templates, scaffolds and heterocyclic ligands to generate novel small molecule drug-like PIs; (d) performance of in-depth drug-resistance studies and determination of X-ray structures of selected inhibitors to gain molecular insight. This research integrates organic synthesis, protein-ligand x-ray crystallography, molecular modeling and in-depth virus and cell-biological studies to design the next generation of HIV-1 protease inhibitors.