Accelerated development of advanced leads against SARS-CoV-2 and other pandemic viruses

加速开发针对 SARS-CoV-2 和其他大流行病毒的先进先导药物

• 批准号: 10513922
• 负责人: David S Perlin
• 金额: $ 388.58万
• 依托单位: HACKENSACK UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-16 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10513922
• 关键词: 2019-nCoV; Active Sites; Advanced Development; Amino Acids; Animal Model; Animals; Antiviral Agents; Binding Proteins; Biochemical; Biological Assay; COVID-19 pandemic; Canis familiaris; Cardiovascular system; Cells; Chemicals; Clinical; Clinical Research; Coronavirus; Development; Dose; Dose Fractionation; Dose-Limiting; Drug Kinetics; Enzymes; Flavivirus; Future; Goals; Hepatitis C virus; Human; In Vitro; Infection; Investigational Drugs; Lead; Libraries; Lung; Metabolic; Methods; Middle East Respiratory Syndrome; Modeling; Monoclonal Antibody Therapy; Mus; Nature; Oral; Outpatients; Parents; Pathogenicity; Peptide Hydrolases; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology; Pharmacology Study; Plasma; Process; Property; Protease Inhibitor; Rattus; Regimen; Replicon; Resistance; Risk; Rodent; Running; SARS coronavirus; Safety; Series; Speed; Structure; System; Therapeutic; Therapeutic Index; Tissues; Toxic effect; Toxicokinetics; Toxicology; Treatment Efficacy; Variant; Viral; Virus; analog; animal coronavirus; animal efficacy; anti-viral efficacy; antiviral drug development; base; clinical candidate; clinical development; drug candidate; drug development; drug discovery; efficacy study; first-in-human; human coronavirus; in silico; in vivo; inhibitor; lead series; metropolitan; mimetics; mouse model; novel coronavirus; pandemic disease; pharmacokinetics and pharmacodynamics; predictive tools; product development; programs; remdesivir; respiratory; response; safety study; scaffold; vaccine development; vaccine-induced antibodies

Abstract There is an urgent need for a safe, highly effective orally bioavailable drug that can be used in the outpatient setting. Ideally, such drugs would have broad-spectrum potential and would be activity against SARS-CoV-2 and other existing and potentially future emergent coronaviruses. A viable strategy to accelerate drug development is repositioning of approved drug and/or existing clinical candidates as chemical scaffolds to create new chemically optimized clinical development candidates. Working in partnership with a team of drug hunters at Merck, focused compound libraries derived from existing antiviral classes discovered/developed against other conserved viral targets and new Lead series to both host and viral targets were screened. The most promising candidates were found to target the main (3CL or MPro) protease. The 3CLpro inhibitors being optimized are peptidyl mimetics of the active site amino acid substrates that were derived from an initial hit boceprevir. Boceprevir is an HCV NS3 protease inhibitor developed by Merck as the first direct acting antiviral used to treat HCV-infection. Initial structure-based optimization of 3CLpro was used to increase analog potency >170-fold relative to the parent compound. Program protease inhibitors now under optimization represent multiple distinct sub-series of new chemical entities. To aid in this process, a robust cell-based SARS-CoV-2 replicon system was established to rapidly evaluate compounds for potency. Lead compounds with inhibitory activity of <10 nM were identified following detailed dose response in EC50,90/CC50 studies yielding therapeutic index ratios >1000. The compounds have suitable pharmacologic development properties and are candidates for animal efficacy studies. The objective of this program is to establish Optimized Leads suitable as oral drug candidates to enter IND enabling studies by 1) finalizing Leads for in vitro potency (IC90 <10 nM; EC50 <10 nM) and safety (CC50 >10 µM) with high therapeutic index >1000; and in vivo lung efficacy against SARS-CoV-2 (TCID50 >5 logs) and other coronaviruses; 2) define PK/PD Relationships, tolerability, resistance, and pre-IND considerations, and 3) perform IND-enabling and de-risking studies. This Program takes advantage of the Merck’s team expertise in developing antiviral drugs and the MAVDA in providing high-end Core support for animal models, resistance assessment, and access to viral models beyond SARS-CoV-2.

摘要 目前迫切需要一种安全、高效、可用于门诊的口服生物利用度药物 设置.理想情况下，此类药物将具有广谱潜力，并将对SARS-CoV-2具有活性 以及其他现有的和未来可能出现的冠状病毒。一个可行的战略，以加快药物 开发是将批准的药物和/或现有的临床候选药物重新定位为化学支架， 新的化学优化的临床开发候选物。与一队缉毒人员合作 在默克，从现有的抗病毒药物类别中发现/开发的重点化合物库， 筛选了其它保守的病毒靶和针对宿主和病毒靶的新的Lead系列。最 发现有希望的候选物靶向主要（3CL或MPro）蛋白酶。3CLpro抑制剂是 优化的是源自初始命中的活性位点氨基酸底物的肽基模拟物 博赛泼维。博西普韦是由默克公司开发的HCV NS 3蛋白酶抑制剂，作为第一种直接作用的抗病毒药物。 用于治疗HCV感染。使用3CLpro的初始基于结构的优化来增加类似物效力 相对于母体化合物的>170倍。目前正在优化的蛋白酶抑制剂程序代表 新化学实体的多个不同子系列。为了帮助这一过程，一个强大的基于细胞的SARS-CoV-2 建立了复制子系统以快速评价化合物的效力。具有抑制活性的先导化合物 在EC 50，90/CC 50研究中，在详细的剂量反应后，确定了<10 nM的活性， 治疗指数比值>1000。所述化合物具有合适的药理学开发性质， 动物功效研究的候选人。该计划的目标是建立合适的优化线索 作为口服候选药物进入IND使能研究，通过1）完成先导化合物的体外效力（IC 90 <10 nM; EC 50 <10 nM）和安全性（CC 50>10 µM），高治疗指数>1000; SARS-CoV-2（TCID 50>5 log）和其他冠状病毒; 2）定义PK/PD关系、耐受性、耐药性， 和IND前考虑，以及3）进行IND启用和降低风险研究。该方案利用 默克团队在开发抗病毒药物方面的专业知识和MAVDA在提供高端核心支持方面的专业知识 用于动物模型、耐药性评估和获得SARS-CoV-2以外的病毒模型。