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.

甲型流感病毒属于正粘病毒科，具有负义、分段RNA 基因组，可引起季节性或大流行性流感，发病率高，死亡率高。 接种疫苗是控制流感感染的最普遍的预防手段。但安 有效的疫苗通常需要至少六个月的时间来研制。此外，疫苗接种限制了 在治疗免疫功能低下的患者中，其有效性也有限 在大流行期间。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， 在2018年，在流感季节尚未尝试。耐NAI菌株的迅速出现， 甲型流感病毒强烈表明，单独的NAI可能不足以作为有效的治疗方法， 因此，迫切需要靶向其它病毒/宿主因子的新的治疗选择。本申请 确定了一项开发有效的小分子抑制剂的计划，该抑制剂可以阻止甲型流感病毒的进入。我们 已经鉴定了抑制传染性甲型流感病毒进入的化合物，其IC 50值在 纳摩尔范围。我们已经合成了抗流感病毒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;验证了先导抑制剂 候选人的感染性试验，并研究了这些的作用机制（MOA） 抑制剂;以及具有优异的体外效力和选择性值的选定的抗流感抑制剂， 类药体内药代动力学特性。在这个快速通道STTR第一和第二阶段的应用，我们建议， 四个具体目标：（1）优化铅支架和选择发展候选人;（2）调查 先进先导化合物与HA蛋白的作用机制（MOA）;（3）评估 先进先导化合物的药代动力学/毒理学;和（4）临床前开发。