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) 是一种艾滋病定义的疾病，有 60-70% 的 HIV 阳性者患有这种疾病，估计全世界每年有 100 万例病例。如果不及时治疗，CM 总是致命的。仅在撒哈拉以南非洲地区，CM 每年就会导致超过 500,000 例 HIV 阳性患者死亡，而普通人群每年因结核病死亡的人数为 350,000 例。由于真菌和人类真核基因组之间的相似性，抗真菌药物发现的一个特殊挑战是毒性。环肽 Aureobasidin A (AbA) 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 相当的杀菌活性。AbA 是肌醇磷酸神经酰胺 1 合酶（IPC1 合酶）的特异性抑制剂肌醇磷酸催化添加到植物神经酰胺中，这是鞘脂途径中的一个步骤真菌中存在，但哺乳动物中不存在。与哺乳动物缺乏 IPC1 合酶相一致，AbA 在礼来公司进行的 I 期临床试验中表现出出色的耐受性 20世纪90年代中期，并已在 CM 动物模型中证明了其功效。 IPC1 合酶的表达对于新型隐球菌以及其他病原真菌（包括白色念珠菌和烟曲霉）的毒力至关重要。使用 AbA 本身作为治疗剂的挑战是该化合物的生物利用度较低。此外，一直缺乏易于处理的化学方法来生成 AbA 类似物，可以测试其配制简易性和改善口服利用度。最近，我们在 Aureogen 的合作者开发了稳健的 2-3 步化学方法来生产 AbA 类似物。与之前用于创建 AbA 类似物进行测试的 21 步化学方法相比，这是显着的改进。一种测试的类似物 AUGC-15 与 AbA 相比，口服利用率提高了 8 倍以上，同时与药物敏感和耐药的新型隐球菌菌株相比，保持了高效和强大的杀菌活性。受这些初步数据的鼓舞，我们希望开发出一种口服的杀菌疗法，以改善 CM 患者的治疗结果。目标 1. 利用初始文库筛选结果和 SAR 设计并合成包含 20 种 IPC1 合酶抑制剂的初始小型文库。目标 2. 筛选和选择具有抗新型隐球菌和格特隐球菌抗真菌活性的化合物，以实现相对于 HepG2 细胞的低细胞毒性和改善的 pk。目标 3. 根据需要根据初始 SAR 迭代库，以实现更广泛的 pk/pd 里程碑并重新测试 20 个其他 IPC1 合酶抑制剂。