Amphotericin B Analogs

两性霉素 B 类似物

• 批准号: 7878264
• 负责人: charles r hutchinson
• 金额: $ 0.84万
• 依托单位: CENTROSE, LLC
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-14 至 2009-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7878264
• 关键词: Acquired Immunodeficiency Syndrome; Acute; Affect; Amphotericin B; Animals; Antifungal Agents; Antifungal Therapy; Aspergillosis; Aspergillus; Azoles; Belief; Biological Assay; Candida; Cell membrane; Chemistry; Classification; Cryptococcus; Cryptococcus neoformans infection; DNA Sequence Rearrangement; Development; Disaccharides; Drug Formulations; Drug Kinetics; Drug resistance; Erythrocytes; Extravasation; Goals; Hematologic Neoplasms; Hemolysis; Immunocompromised Host; In Vitro; Incidence; Infection; Inhibitory Concentration 50; Intravenous; Ions; Kidney; Lead; Libraries; Liposomes; Macrolide Antibiotics; Membrane; Meningitis; Modeling; Modification; Monosaccharides; Mucormycosis; Mycoses; Organ Transplantation; Parents; Pharmaceutical Preparations; Phase; Polyenes; Research; Rodent; Route; Screening Result; Small Business Innovation Research Grant; Structure; Systemic infection; Technology; Testing; Toxic effect; Work; Zygomycosis; amino group; analog; base; candidemia; design; fungus; improved; in vitro activity; in vivo; lipophilicity; member; methylamphotericin B; mycaminose; nephrotoxicity; novel; pathogen; pharmacokinetic characteristic; pre-clinical; programs; public health relevance; small molecule; small molecule libraries; sugar; surfactant; water solubility

DESCRIPTION (provided by applicant): Current antifungal therapy is limited by the types of drugs available to treat systemic infections due to emerging and comparatively rare fungi different from the common strains of pathogenic Candida, Aspergillus, Cryptococcus and the Zygomycoses. Neutropenic and immunocompromised patients, such as those with hematologic cancer, AIDS or an organ transplant, are especially prone to invasive fungal infection. Amphotericin B (AMB) continues to be an important drug for invasive aspergillosis, candidemia, mucormycosis, fusariosis and Cryptococcosis meningitis because of its potency, broad spectrum of activity and the low incidence of drug resistance associated with its use. Nonetheless, the well-known nephrotoxicity of AMB severely limits long term use of this polyene macrolide antibiotic. The toxicity is related to AMB's high lipophilicity, which causes it to localize in cell membranes, disrupting membrane integrity and causing leakage of ions. The structural alterations of AMB carried out to date have not resulted in an approved drug that retains the potency and activity spectrum of the parent drug while minimizing its nephrotoxicity and improving its water solubility for ease of formulation. Centrose proposes to use its CarboConnectTM technology for rapidly synthesizing libraries of small molecules with attached sugars of diverse structure to seek novel AMB analogs with lesser toxicity and greater water solubility, together with sufficient potency and spectrum of activity. Precedents among other types of small molecule drugs for improvement of their potency and pharmacokinetics (PK), or diminishment of their toxic liability, by sugar addition or modification provide additional support for our belief that attractive AMB analogs can be discovered in this way. Our rapid, empirical approach to drug lead discovery is sensible for a molecule in which the existing sugar is known to be vital for antifungal activity, yet for which the models of the mechanism of action are inadequate to design a structure-based rationale for systematic exploration and drug lead identification. Assays of library members for antifungal potency and spectrum of activity in vitro together with the results of an in vitro surrogate assay for potential nephrotoxicity should allow identification of leads for in vivo testing. That will involve determining the acute nephrotoxicity, antifungal efficacy and PK characteristics in a rodent. The specific aims of Phase are: 1) to synthesize a 50 member library of sugar conjugates representing a diverse array of mono- and disaccharides from the 19- oximino-OCH2CH2N(H)OCH3 derivative of AMB methyl ester aglycon; 2) to examine the feasibility of synthesizing a 40 member library of 3'-N-glycosyl derivatives of AMB methyl ester by the Amidori rearrangement using novel monosaccharides; 3) to screen the resulting neoglycosides and 3'-N-sugar conjugates for antifungal activity in vitro (MIC values) against a panel of six important fungal pathogens; 4) to determine the IC50 for red blood cell hemolysis of the compounds with MIC's =5 micrograms/ml as a surrogate for in vivo nephrotoxicity; and 5) based on all of the results, to select up to 5 AMB analogs for determination of their acute nephrotoxicity, antifungal activity against two fungal pathogens and PK characteristics in a rodent. PUBLIC HEALTH RELEVANCE:The research aims to discover new forms of the broad spectrum antifungal drug, amphotericin B, with lesser toxicity and greater water solubility, together with sufficient potency and spectrum of activity to be selected for development into an new antifungal drug.

描述（由申请人提供）：目前的抗真菌治疗受到可用于治疗全身感染的药物类型的限制，全身感染是由于新出现的和相对罕见的真菌，不同于常见的致病性念珠菌、曲霉菌、隐球菌和接合菌。中性粒细胞减少症和免疫功能低下的患者，如血液癌症、艾滋病或器官移植患者，特别容易发生侵袭性真菌感染。两性霉素B（AMB）由于其强效、广谱活性和与其使用相关的低耐药性发生率，仍然是侵袭性曲霉病、念珠菌血症、毛霉菌病、镰刀菌病和隐球菌性脑膜炎的重要药物。尽管如此，众所周知的AMB肾毒性严重限制了这种多烯大环内酯抗生素的长期使用。毒性与AMB的高亲脂性有关，这导致其定位于细胞膜中，破坏膜完整性并导致离子泄漏。迄今为止进行的AMB的结构改变尚未导致获得批准的药物保留母体药物的效力和活性谱，同时最大限度地减少其肾毒性并改善其水溶性以便于配制。Centrose建议使用其CarboConnectTM技术快速合成具有不同结构的连接糖的小分子库，以寻求具有更小毒性和更大水溶性的新型AMB类似物，以及足够的效力和活性谱。在其他类型的小分子药物中，通过糖的添加或修饰来改善其效力和药代动力学（PK）或减少其毒性倾向的先例为我们的信念提供了额外的支持，即可以以这种方式发现有吸引力的AMB类似物。我们的快速，经验的方法，药物铅发现是明智的分子，其中现有的糖已知是至关重要的抗真菌活性，但其中的作用机制的模型是不足以设计一个基于结构的理由系统的探索和药物铅识别。库成员的体外抗真菌效力和活性谱测定以及潜在肾毒性的体外替代测定结果应允许鉴定体内试验的先导化合物。这将涉及确定啮齿动物中的急性肾毒性、抗真菌疗效和PK特征。Phase的具体目标是：1）从AMB甲酯糖苷配基的19-肟基-OCH 2CH 2N（H）OCH 3衍生物合成代表各种单糖和二糖的50个成员的糖缀合物文库; 2）研究使用新单糖通过Amidori重排合成AMB甲酯的3 '-N-糖基衍生物的40个成员文库的可行性; 3）体外筛选新糖苷类和3 ′-N-糖缀合物的抗真菌活性4）确定化合物的红细胞溶血的IC 50，其中MIC =5微克/ml作为体内肾毒性的替代物;和5）基于所有结果，选择多达5种AMB类似物用于测定它们在啮齿动物中的急性肾毒性、对两种真菌病原体的抗真菌活性和PK特征。公共卫生相关性：该研究旨在发现新形式的广谱抗真菌药物，阿替西霉素B，具有较低的毒性和更大的水溶性，以及足够的效力和活性谱，以选择开发成一种新的抗真菌药物。