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）：隐球菌脑膜炎（CM）是60-70%的HIV阳性个体的艾滋病定义疾病，估计全球每年发生100万例。如果不治疗，CM总是致命的。仅在撒哈拉以南非洲，CM每年在HIV阳性患者中导致超过500，000人死亡，而在普通人群中每年有350，000人死于结核病。由于真菌和人类真核生物基因组之间的相似性，发现抗真菌药物的一个特殊挑战是毒性。环肽Aureobasidin A（阿坝）于1992年由Takara Shuzo获得专利，是一种强效化合物，对新型隐球菌具有与两性霉素B相当的强效杀真菌活性。阿坝是肌醇磷酸神经酰胺1合酶（IPC 1合酶）催化的肌醇磷酸加成到植物神经酰胺的特异性抑制剂，这是真菌中鞘脂途径中的一个步骤，但在哺乳动物中不存在。与哺乳动物中缺乏IPC 1合酶一致，阿坝在Eli Lilly进行的I期临床试验中表现出极好的耐受性 在20世纪90年代中期，并且已经在CM的动物模型中证明了功效。IPC 1合成酶的表达对C.新生菌以及其它致病真菌，包括白色念珠菌和烟曲霉。采用阿坝本身作为治疗剂的挑战是该化合物的生物利用度低。此外，一直缺乏易处理的化学方法来产生阿坝类似物，其可以被测试配制的容易性和改善的口服利用度。最近，我们在Aureogen的合作者已经开发出稳健的2-3步化学方法来生产阿坝A类似物。这是对用于产生用于测试的阿坝类似物的先前21步化学的显著改进。测试的一种类似物AUGC-15与阿坝相比表现出> 8倍的改善的口服利用度，同时与药物敏感和药物抗性的念珠菌菌株相比保持高效力和稳健的杀真菌活性。新人类在这些初步数据的鼓舞下，我们希望开发一种口服的杀真菌治疗药物，以改善CM患者的治疗效果。目标1.采用初始文库筛选结果和SAR设计并合成20种IPC 1合酶抑制剂的初始小文库。目标2.筛选和选择具有抗念珠菌活性的化合物。新型隐球菌和gattii相对于HepG 2细胞的低细胞毒性和改善的pk.目标3.根据需要基于初始SAR迭代文库，以实现更广泛的pk/pd里程碑，并重新测试20种额外的IPC 1合酶抑制剂。