New antifungals targeting the synthesis of fungal sphingolipids

摘要 这项题为“合成真菌鞘脂的新型抗真菌药物”的提案更新的最终目标是 为了继续优化我们使用上一个资金周期产生的第三代化合物， 最终目标是在更新结束时让1-5种化合物进行临床前研究并提交研究用新药 (IND)与食品药物管理局(FDA)合作治疗侵袭性真菌感染(IFI)。国际金融机构越来越多地 对严重危及生命的情况负责，特别是免疫力受损的个人。在过去的10年里， 我们一直致力于研究和开发一类新的抗真菌药物，针对合成 真菌，但不是哺乳动物的鞘脂。N’-(3-bromo-6-hydroxybenzylidene)-2-methylbenzohydrazide的初步发现 (BHBM)作为图书馆筛选出的热门化合物，我们启动了一项密集的研究计划，涉及 BHBM衍生物的组合/平行合成和构效关系的评估。本节目 使我们能够合成比目前临床上使用的抗真菌药物更有效的第三代化合物。 我们的第三代化合物已获得知识产权(IP)和一家初创公司(MicroRid Technologies Inc.)与许可选项是共同资助的，带来了必要的专业知识来进一步开发这些有效的抗真菌药物 化合物。我们现在寻求在不失去抗真菌活性的情况下优化药代动力学、毒理学特性。我们发起了 合成数百种化合物以产生基于D13的第三代化合物(目标1)，将进行评估 用于抗真菌活性和作用机制(目标2)。一些选定的化合物将接受毒理学和密集的 PK研究(目标3)，最终将有一种化合物被选为IND备案。我们的经验、专业知识和持续发展 在这一抗真菌研究领域的努力以及石溪大学、长岛高科技 孵化器和MicroRid Technologies Inc.使我们处于实现这些目标的非常独特的地位。

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.