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 迫切需要一种安全、高效的口服生物利用药，可用于门诊患者。 布景。理想情况下，这种药物将具有广谱潜力，并具有对抗SARS-CoV-2的活性。 以及其他现有的和未来可能出现的冠状病毒。加速药物开发的可行策略 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，以创建 新的化学优化临床开发候选者。与一个毒品猎人团队合作 在默克公司，从现有抗病毒类别衍生的重点化合物文库被发现/开发用于治疗 筛选了其他保守的病毒靶点和针对宿主和病毒靶点的新的前导系列。最多的 有希望的候选者被发现以主要(3CL或MPRO)蛋白酶为靶标。3CLPRO抑制剂是 优化的是活性部位氨基酸底物的多肽模拟物，这些底物来自最初的打击 博西普利韦。博西普利韦是默克公司开发的第一个直接作用的抗病毒药物，是一种丙型肝炎病毒NS3蛋白酶抑制剂 用于治疗丙型肝炎病毒感染。3CLPro采用基于初始结构的优化来提高模拟效率 &gt；是母体化合物的170倍。正在优化中的程序化蛋白酶抑制剂代表 多个不同的新化学实体的子系列。为了帮助这一过程，一种强大的基于细胞的SARS-CoV-2 为了快速评价化合物的效力，建立了复制子系统。具有抑制作用的先导化合物 在EC50，90/CC50研究中，根据详细的剂量反应确定了&lt；10 nM的活性 治疗指数比&gt；1000。这些化合物具有适当的药理开发特性，并且 动物功效研究的候选对象。该计划的目标是建立合适的优化销售线索 作为口服药物候选者进入IND使能研究1)最终确定体外效力的线索(IC90和lt；10 NM； EC50；10 NM)和安全性(CC50；10微米)，具有较高的治疗指数&GT；1000；以及活体肺对抗肿瘤药物的疗效 SARS-CoV-2(TCID50；>5 Logs)和其他冠状病毒；2)定义PK/PD关系、耐受性、耐药性、 和IND前的考虑，以及3)执行IND启用和降低风险研究。该计划利用了 默克在开发抗病毒药物方面的团队专业知识和MAVDA在提供高端核心支持方面的专业知识 对于动物模型，耐药性评估，以及获得SARS-CoV-2以外的病毒模型。