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.

抽象的 迫切需要一种可在门诊使用的安全、高效的口服生物利用药物 理想情况下，此类药物应具有广谱潜力，并且具有抗 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，是加速药物研发的可行策略。 开发是将已批准的药物和/或现有的临床候选药物重新定位为化学支架，以创建 与药物研发团队合作，进行新的化学优化临床开发候选药物。 在默克，重点化合物库源自发现/开发的现有抗病毒类别 筛选了其他保守的病毒靶标以及针对宿主和病毒靶标的新先导系列。 发现有希望的候选物以主要（3CL 或 MPro）蛋白酶 3CLpro 抑制剂为目标。 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 博普瑞韦是默克公司开发的一种 HCV NS3 蛋白酶抑制剂，是第一种直接作用的抗病毒药物。 用于治疗 HCV 感染。 3CLpro 的初始结构优化用于提高类似物的效力。 相对于母体化合物，程序蛋白酶抑制剂现在提高了 170 倍。 为了帮助这一过程，我们开发了一种强大的基于细胞的 SARS-CoV-2。 建立复制子系统以快速评估具有化合物抑制作用的先导化合物的效力。 根据 EC50,90/CC50 研究中的详细剂量反应，确定了 <10 nM 的活性 治疗指数比>1000 该化合物具有合适的药理学开发特性并且是 该计划的目标是建立适合动物功效研究的候选者。 作为进入 IND 的口服候选药物，通过以下方式进行研究：1) 最终确定体外效力的先导化合物（IC90 <10 nM； EC50 <10 nM）和安全性（CC50 >10 µM），治疗指数 >1000；体内肺功效 SARS-CoV-2（TCID50 > 5 个对数）和其他冠状病毒；2) 定义 PK/PD 关系、耐受性、耐药性、 和 IND 前的考虑因素，以及 3) 进行 IND 启用和去风险研究。 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、耐药性评估以及获取 SARS-CoV-2 以外的病毒模型。