Development of 4-(aroylamino)piperidine-based entry inhibitors as anti-influenza therapeutics

开发基于 4-(芳酰氨基)哌啶的进入抑制剂作为抗流感疗法

基本信息

批准号：
10256145
负责人：
Lijun Rong
金额：
$ 30万
依托单位：
CHICAGO BIOSOLUTIONS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-02 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10256145
关键词：
Acute Address Affinity Amantadine Animal Model Antidotes Antiviral Agents Binding Biochemical Biological Biological Assay Canis familiaris Characteristics Chemicals Clinical Research Code Communicable Diseases Crystallization Development Dose Drug Design Drug Kinetics Effectiveness Epidemic Evaluation Exhibits Family Future Genome Goals Hemagglutinin Immunocompromised Host In Vitro Infection Influenza Influenza A Virus, H5N1 Subtype Influenza A virus Influenza Therapeutic Integration Host Factors Lead Libraries Life Cycle Stages Maximum Tolerated Dose Mediating Methods Modeling Morbidity - disease rate Mus Mutation Neuraminidase inhibitor Oral Orthomyxoviridae Oseltamivir Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacology Pharmacology and Toxicology Phase Plasma Polymerase Property Proteins RNA Rattus Research Resistance Resolution Rimantadine Rodent Route Safety Seasons Series Small Business Technology Transfer Research Specificity Structure Structure-Activity Relationship Surface Testing Therapeutic Therapeutic Uses Time Toxic effect Toxicokinetics Toxicology Treatment Efficacy Vaccination Vaccines Viral Virulent Virus Virus Diseases Virus Replication X-Ray Crystallography analog anti-influenza base design drug development effective therapy efficacy evaluation endonuclease experimental study flu genotoxicity improved in vivo in vivo evaluation influenza M2 influenza infection influenza virus strain inhibitor/antagonist ion channel blocker lead optimization mortality mouse model mutant nanomolar neutralizing antibody novel therapeutics pandemic disease pandemic influenza piperidine pre-clinical preclinical development prophylactic resistant strain safety study safety testing scaffold seasonal influenza small molecule small molecule inhibitor targeted treatment zanamivir

项目摘要

Influenza A viruses belong to the orthomyxoviridae family, and have a negative-sense, segmented RNA genome, which can cause seasonal or pandemic flu with high morbidity and significant mortality. Vaccination is the most prevalent prophylactic means for controlling influenza infections. However, an effective vaccine usually takes at least six months to develop. Furthermore, vaccination has limited effectiveness in the treatment of immunocompromised patients, and its effectiveness is also limited during a pandemic. The current therapeutic options for flu infections are all based on the neuraminidase inhibitors (NAIs; oseltamivir, zanamivir and peramivir), while the influenza M2 ion channel blockers (amantadine and rimantadine) are not now recommended since all of the circulating influenza strains have acquired resistance. (Xofluza, a polymerase acidic endonuclease inhibitor, has just been approved in 2018 and is yet untried during a flu season.) The rapid emergence of the NAI-resistant strains of influenza A viruses strongly suggests that NAIs alone may not be sufficient as effective therapies, and thus new treatment options targeting the other viral/host factors are urgently needed. This application defines a plan to develop potent, small molecule inhibitors, which block entry of influenza A viruses. We have identified compounds that inhibit entry of infectious influenza A viruses, with IC50 values in the nanomolar range. We have synthesized structurally diverse analogs of the anti-influenza hit series using structure-activity relationships (SARs) to improve potency and selectivity; validated the lead inhibitor candidates in the infectious assay and investigated the mechanism of action (MOA) of the these inhibitors; and selected anti-influenza inhibitors with excellent in vitro potency and selectivity values and druglike in vivo pharmacokinetic properties. In this Fast Track STTR Phase I &II application, we propose four specific aims: (1) optimize the lead scaffold and select development candidates; (2) investigate the mechanism of action (MOA) of the advanced lead compounds with HA proteins; (3) evaluate the pharmacokinetics/toxicokinetics of the advanced lead compounds; and (4) preclinical development.

甲型流感病毒属于正粘病毒科，具有负义、分段 RNA 基因组，可能导致季节性或大流行性流感，发病率高，死亡率高。疫苗接种是控制流感感染最普遍的预防手段。然而，一个有效的疫苗通常需要至少六个月的时间才能开发出来。此外，疫苗接种也受到限制对免疫功能低下患者的治疗效果不佳，而且效果也有限大流行期间。目前流感感染的治疗选择都是基于神经氨酸酶抑制剂（NAIs；奥司他韦、扎那米韦和帕拉米韦），而流感 M2 离子通道阻滞剂（金刚烷胺和金刚乙胺）现在不推荐，因为所有流行的流感病毒株已经获得了抵抗力。（Xofluza，一种聚合酶酸性核酸内切酶抑制剂，刚刚获得批准 2018 年，流感季节期间尚未尝试过。） NAI 抗性菌株的迅速出现甲型流感病毒强烈表明，单独使用 NAI 可能不足以作为有效的治疗方法，并且因此，迫切需要针对其他病毒/宿主因素的新治疗方案。这个应用程序制定了开发有效的小分子抑制剂的计划，该抑制剂可阻止甲型流感病毒的进入。我们已鉴定出可抑制传染性甲型流感病毒进入的化合物，IC50 值为纳摩尔范围。我们使用以下方法合成了抗流感热门系列的结构多样的类似物结构-活性关系（SAR）以提高效力和选择性；验证先导抑制剂感染性测定中的候选者并研究了这些药物的作用机制（MOA）抑制剂；并选择具有优异体外效力和选择性值的抗流感抑制剂，类似药物的体内药代动力学特性。在此快速通道 STTR 第一期和第二期申请中，我们建议四个具体目标：（1）优化先导支架并选择开发候选者； (2) 调查具有HA蛋白的先进先导化合物的作用机制（MOA）； (3) 评估先进先导化合物的药代动力学/毒代动力学； (4)临床前开发。