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

• 批准号: 10618383
• 负责人: Lijun Rong
• 金额: $ 99.94万
• 依托单位: CHICAGO BIOSOLUTIONS, INC.
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-02 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10618383
• 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; Recommendation; Research; Resistance; Resolution; Rimantadine; Rodent; Route; Safety; 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; design; drug development; effective therapy; efficacy evaluation; endonuclease; experimental study; genotoxicity; improved; in vivo; in vivo evaluation; influenza M2; influenza infection; influenza virus strain; inhibitor; 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; synergism; targeted treatment; zanamivir

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.

流感病毒属于矫形病毒家族，具有负态，分割的RNA 基因组，可能引起季节性或大流行流感，具有高发病率和显着的死亡率。 疫苗接种是控制流感感染的最普遍的预防手段。但是，一个 有效的疫苗通常至少需要六个月才能开发。此外，疫苗接种有限 在治疗免疫功能低下的患者方面的有效性，其有效性也受到限制 在大流行期间。流感感染的当前治疗选择均基于神经氨酸酶 抑制剂（NAIS； Oseltamivir，Zanamivir和Peramivir），而流感M2离子通道阻滞剂 现在不建议（amantadine和rimantadine），因为所有循环流感菌株 已经获得了阻力。 （Xofluza是一种聚合酶酸性内切核酸酶抑制剂，刚刚批准 在2018年，在流感季节仍未尝试。） 流感病毒强烈表明，单独的NAI可能不足以作为有效的疗法，并且 因此，迫切需要针对其他病毒/宿主因素的新治疗方案。此应用程序 定义了开发有效的小分子抑制剂的计划，该抑制剂阻断了流感病毒的进入。我们 已经鉴定出抑制传染性流感A病毒的化合物，其中IC50值 纳摩尔范围。我们使用了使用抗激素命中系列的结构上的类似物合成的。 结构活动关系（SARS）以提高效力和选择性；验证铅抑制剂 传染性测定中的候选人并研究了这些作用机理（MOA） 抑制剂；并选择具有出色体外效力和选择性值的抗激素抑制剂 药物中的体内药代动力学特性。在这个快速的sttr I阶段I和II应用程序中，我们提出了 四个具体目的：（1）优化铅支架并选择候选者； （2）调查 带有HA蛋白的晚期铅化合物的作用机理（MOA）； （3）评估 高级铅化合物的药代动力学/毒性动力学； （4）临床前发展。