Discovering a Targeted Inositol Phosphorylceramide Synthase Inhibitor to Improve

发现一种靶向肌醇磷酸神经酰胺合酶抑制剂来改善

• 批准号: 8732202
• 负责人: MITCHELL W MUTZ
• 金额: $ 22.5万
• 依托单位: AMPLYX PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-02-05 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8732202
• 关键词: Acquired Immunodeficiency Syndrome; Acute; Adverse effects; Africa; Africa South of the Sahara; AmBisome; Amphotericin B; Animal Model; Antifungal Agents; Arrhythmia; Aspergillus fumigatus; Biological Availability; Candida albicans; Cell Survival; Cells; Ceramides; Cessation of life; Chemicals; Chemistry; Cryptococcal Meningitis; Cryptococcus; Cryptococcus neoformans; Cryptococcus neoformans infection; Cyclic Peptides; Data; Drug Formulations; Drug resistance; Exhibits; Fluconazole; Flucytosine; General Population; Generic Drugs; Genome; Goals; HIV; HIV Seropositivity; Health; Human; Incidence; Individual; Industrial fungicide; Infection; Inositol; Left; Legal patent; Leukopenia; Libraries; Lipids; Liposomes; Maintenance Therapy; Mammals; Methods; Neoadjuvant Therapy; North America; Oral; Pathway interactions; Patients; Permeability; Pharmaceutical Preparations; Phase I Clinical Trials; Property; Protons; Relative (related person); Sales; Screening Result; Southeastern Asia; Specificity; Sphingolipids; Testing; Therapeutic; Toxic effect; Transplant Recipients; Treatment Protocols; Treatment outcome; Tuberculosis; Virulence; analog; aureobasidin A; base; compliance behavior; cost effective; cytotoxicity; design; fungus; improved; inhibitor/antagonist; mortality; nephrotoxicity; public health relevance; resistant strain; theories

DESCRIPTION (provided by applicant): Cryptococcal meningitis (CM) is the AIDS-defining illness for 60-70% of HIV positive individuals with an estimated worldwide occurrence of 1 million cases annually. CM is invariably fatal if left untreated, In sub-Saharan Africa alone, CM causes over 500,000 annual deaths among HIV positive patients compared with 350,000 annual deaths for tuberculosis in the general population. A particular challenge with the discovery of antifungal drugs is toxicity due to the similarities between the fungal and human eukaryotic genomes. The cyclic peptide, Aureobasidin A (AbA), patented in 1992 by Takara Shuzo, is a potent compound with strong, fungicidal activity vs. Cryptococcus neoformans comparable to Amphotericin B. AbA is a specific inhibitor of the inositol phosphorylceramide 1 synthase (IPC1 synthase) catalyzed addition of inositolphosphate to phytoceramide, a step in the sphingolipid pathway in fungi but absent in mammals. Consistent with the lack of IPC1 synthase in mammals, AbA demonstrated excellent tolerability in a Phase I clinical trial performed by Eli Lilly in the mid 1990's and has demonstrated efficacy in animal models of CM. Expression of IPC1 synthase is essential for virulence in C. neoformans, as well as other pathogenic fungi including Candida albicans and Aspergillus fumigatus. The challenge with employing AbA itself as a therapeutic is the low bioavailability of the compound. Moreover, there has been a lack of tractable chemical methods to generate AbA analogues that can be tested for ease of formulation and improved oral availability. Recently, our collaborators at Aureogen have developed robust, 2-3 step chemistries to produce analogues of AbA. This is remarkable improvement over the prior 21 step chemistries employed to create AbA analogues for testing. One analogue tested, AUGC-15, exhibited > 8-fold improved oral availability vs. AbA while maintaining high potency and robust fungicidal activity vs. drug susceptible and drug resistant strains of C. neoformans. Encouraged by these preliminary data, we hope to develop an orally available, fungicidal therapeutic to improve treatment outcomes for CM patients. Aim 1. Employ initial library screening results and SAR to design and synthesize an initial small library of 20 IPC1 synthase inhibitors. Aim 2. Screen and select compounds for antifungal activity against C. neoformans and C. gattii for low cytoxicity vs. HepG2 cells and improved pk. Aim 3. Iterate library as needed based on initial SAR as needed to achieve more extensive pk/pd milestones and retest 20 additional IPC1 synthase inhibitors.

描述(由申请人提供)：隐球菌性脑膜炎(CM)是60-70%艾滋病毒阳性患者的艾滋病定义疾病，估计全球每年发生100万例。如果不加以治疗，CM总是致命的，仅在撒哈拉以南非洲，CM每年就导致50多万艾滋病毒阳性患者死亡，而普通人群每年死于结核病的人数为350,000人。发现抗真菌药物的一个特别挑战是由于真菌和人类真核基因组之间的相似性而产生的毒性。环肽Aureobasidin A(ABA)于1992年由Takara Shuzo申请专利，是一种具有强大杀菌活性的化合物，对新生隐球菌的杀菌活性与两性霉素B相当。ABA是肌醇磷酸神经酰胺1合成酶(IPC1合成酶)的特异性抑制剂，IPC1合成酶催化肌醇磷酸与植神经酰胺的加成，这是真菌中鞘磷脂途径中的一个步骤，但在哺乳动物中不存在。与哺乳动物缺乏IPC1合成酶一致，ABA在礼来公司进行的I期临床试验中表现出极好的耐受性 S在20世纪90年代中期提出，并在CM的动物模型上证明了其有效性。IPC1合酶的表达对新生葡萄球菌以及包括白色念珠菌和烟曲霉菌在内的其他病原真菌的毒力是必不可少的。使用ABA本身作为治疗药物的挑战是该化合物的低生物利用度。此外，一直缺乏易操作的化学方法来产生ABA类似物，这些方法可以进行测试，以便于配方和提高口服利用度。最近，我们在Aureogen的合作伙伴已经开发出强大的2-3步化学方法来生产ABA的类似物。这比之前用于创建用于测试的ABA类似物的21步化学方法有了显着的改进。一种被测试的类似物，AUGC-15，显示出与ABA相比口服利用度提高了8倍，同时与药物敏感和耐药的新生芽孢杆菌菌株相比，保持了高效和强大的杀菌活性。在这些初步数据的鼓舞下，我们希望开发一种口服的杀菌疗法来改善CM患者的治疗结果。目的1.利用初步的文库筛选结果和SAR，设计并合成一个包含20个IPC1合成酶抑制剂的初始小文库。目的：筛选抗新生葡萄球菌和加蒂革兰氏菌活性的化合物，用于低细胞毒性和改良的PK。目的3.根据需要在初始SAR的基础上根据需要迭代文库，以实现更广泛的PK/PD里程碑，并重新测试另外20种IPC1合成酶抑制剂。