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New antifungals targeting the synthesis of fungal sphingolipids

针对真菌鞘脂合成的新型抗真菌药物

基本信息

批准号：
10596530
负责人：
Maurizio Del Poeta
金额：
$ 76.78万
依托单位：
STATE UNIVERSITY NEW YORK STONY BROOK
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-12-01 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10596530
关键词：
3-Dimensional Academia Acceleration Address Animal Model Animals Antifungal Agents Area Aspergillosis Aspergillus Aspergillus fumigatus Candida Candidiasis Cause of Death Cell physiology Clinic Clinical Collaborations Cryptococcosis Cryptococcus Cryptococcus neoformans Development Drug Design Drug Kinetics Drug Modelings Evaluation Exhibits Fluconazole resistance Funding Generations Goals Human Immunity Immunocompromised Host In Vitro Incubators Individual Industry Infection Intellectual Property Investigation Investigational Drugs Lead Libraries Licensing Life Long Island Medical Mus Mycoses Pathogenesis Pathway interactions Pharmaceutical Chemistry Pharmacologic Substance Physicians Physiology Positioning Attribute Property Quantitative Structure-Activity Relationship Research Resistance Resistant candida Safety Scientist Secure Series Sphingolipids Structure-Activity Relationship Technology Testing Therapeutic Toxic effect Toxicology Translating United States Food and Drug Administration Universities clinical candidate clinical efficacy combinatorial cross reactivity drug development drug discovery efficacy study experience fungicide fungus improved in vivo in vivo evaluation indexing inhibitor innovation lead optimization novel novel therapeutic intervention pathogenic fungus pharmacologic preclinical study programs research and development screening

项目摘要

ABSTRACT The ultimate goal of this proposal renewal entitled, “New antifungals targeting the synthesis of fungal sphingolipids”, is to continue the optimization of our 3rd generation compounds that we generated using the previous funding cycle, with the ultimate goal to subject 1-5 compounds at the end of the renewal to preclinical studies and file an Investigational New Drug (IND) with the Food Drug Administration (FDA) for the treatment of invasive fungal infections (IFI). IFIs are increasingly responsible for serious life-threatening conditions, particularly in individuals with compromised immunity. For the past 10 years, we have been working on the research and development of a new class of antifungal agents directed against the synthesis of fungal but not mammalian sphingolipids. The initial discovery of N’-(3-bromo-6-hydroxybenzylidene)-2-methylbenzohydrazide (BHBM) as the hit compound from library screening lead us to initiate an intensive research program involving the combinatorial/parallel synthesis of BHBM derivatives and the assessment of a structure-activity relationship. This program allowed us to synthesize a 3rd-generation compounds more efficacious than the antifungals currently used in the clinic. Our 3rd-generation compounds have secured intellectual property (IP) and a start-up company (MicroRid Technologies Inc.) with licensing options was co-funded, bringing the necessary expertise to further develop these potent antifungal compounds. We now seek to optimize pharmacokinetics, toxicology properties without losing antifungal activity. We initiated the synthesis of several hundred compounds to create a 3rd generation compounds based on D13 (Aim 1) that will be assessed for antifungal activity and mechanism of action (Aim 2). A few selected compounds will be subjected to toxicology and intensive PK studies (Aim 3), and, finally, one compound will ultimately be selected for IND filing. Our experience, expertise, and ongoing effort in this area of antifungal research and the partnership between Stony Brook University, the Long Island High Tech Incubator, and MicroRid Technologies Inc. place us in a very unique position to achieve these goals.

摘要