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）是定义艾滋病疾病的艾滋病毒疾病，其中60-70％的艾滋病毒阳性个体每年在全球范围内估计发生100万例。 CM总是致命的，如果未经治疗，仅在撒哈拉以南非洲，CM就会导致艾滋病毒阳性患者每年500,000多人死亡，而每年350,000人死亡的一般人群死亡。发现抗真菌药物的一个特殊挑战是由于真菌和人类真核基因组之间的相似性，毒性。 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，是真菌鞘脂途径的一步，但在哺乳动物中不存在。与哺乳动物中缺乏IPC1合酶一致，在Eli Lilly进行的I期临床试验中，ABA表现出极好的耐受性 在1990年代中期，在CM动物模型中表现出了功效。 IPC1合酶的表达对于Neoformans以及包括白色念珠菌和曲曲霉的其他致病真菌中的毒力至关重要。将ABA本身作为治疗性的挑战是该化合物的生物利用度低。此外，缺乏可拖动的化学方法来产生ABA类似物，这些ABA类似物可以进行测试，以易于配方和改善口服可用性。最近，我们在Auregen的合作者开发了强大的2-3个步骤化学，以产生ABA的类似物。这是对以前的21个步骤化学作品来创建ABA类似物进行测试的显着改善。一项测试的模拟于8月15日，与ABA相比，口服可用性提高了> 8倍，同时保持了高效力和稳健的杀真菌活性，而易感性和耐药性菌株的Neoformans菌株。在这些初步数据的鼓励下，我们希望开发一种口服，杀真菌治疗，以改善CM患者的治疗结果。 AIM 1。采用初始库筛选结果和SAR设计和合成20个IPC1合酶抑制剂的初始小库。 AIM 2。筛查和选择针对Neoformans的抗真菌活性的化合物和低细胞毒性与HEPG2细胞的抗真菌活性，并改善了PK。 AIM 3。根据需要根据需要的初始SAR迭代库，以实现更广泛的PK/PD里程碑，并重新测试20个额外的IPC1合成酶抑制剂。