Optimization of orally bioavailable inhibitors for the treatment of COVID-19 and other human coronavirus infections

用于治疗 COVID-19 和其他人类冠状病毒感染的口服生物可利用抑制剂的优化

基本信息

批准号：
10698831
负责人：
Glen Andrew Coburn
金额：
$ 100万
依托单位：
VENATORX PHARMACEUTICALS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-06-07 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10698831
关键词：
2019-nCoV Acceleration Acute Acute Respiratory Distress Syndrome Address Ames Assay Animals Antiviral Agents Biological Biological Availability COVID-19 COVID-19 treatment Caco-2 Cells Canis familiaris Case Fatality Rates Cell Culture System Cell Line Cessation of life Chemicals Clinical Complement Coronavirus Coronavirus Infections Development Dose Drug Design Drug Evaluation Drug Interactions Drug Kinetics Epidemic Exposure to Future Goals Healthcare Systems Hepatocyte Human In Vitro Individual Infection Intervention Intestines Lead Maximum Tolerated Dose Microsomes Middle East Respiratory Syndrome Coronavirus Modeling Molecular Target Mus Mutagenicity Tests Oral Patients Pattern Paxlovid Permeability Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacology Study Phase Plasma Population Positioning Attribute Predisposition Prevention Property Protein Isoforms Public Health Publishing Rattus Resistance Resistance profile Respiratory Disease Risk SARS coronavirus SARS-CoV-2 entry inhibitor SARS-CoV-2 infection Safety Series Small Business Innovation Research Grant Solubility Stress Symptoms Therapeutic Toxic effect Toxicology Vaccines Variant Viral Viral Physiology Viral Pneumonia Virus World Health antagonist candidate selection coronavirus disease cytotoxic drug discovery drug repurposing experience future outbreak genotoxicity global health high throughput screening human coronavirus improved in vivo inhibitor lead optimization meter nirmatrelvir novel novel coronavirus pandemic coronavirus pandemic disease pandemic potential patient population patient subsets pill respiratory safety study scale up screening small molecule small molecule inhibitor spillover event technique development zoonotic coronavirus

项目摘要

PROJECT SUMMARY The emergence of SARS-CoV-2 in 2019 has resulted in an ongoing epidemic of acute respiratory illness that has stressed the world’s health care systems and led to >6 million deaths. The lack of therapeutic options for treating coronavirus infections continues to expose the population to grave risk from emerging variants as well as future zoonotic coronavirus infections. Accelerated drug discovery/development techniques, including drug repurposing and fast follower drug design have only resulted in the approval of a single orally bioavailable inhibitor. Nirmatrelvir/Paxlovid is contraindicated in a large fraction of patients, susceptible to emerging resistant variants and may not demonstrate cross-activity against future coronavirus threats. Therefore, future efforts should focus on the development of new antivirals including those that possess complementary mechanisms of action and resistance profiles. During this Phase 2 project, we will execute a medicinal chemistry/profiling strategy and complete optimization of a novel series of SARS-CoV-2 entry inhibitors to improve their antiviral activity against SARS-CoV-2 and other coronaviruses as well as their pharmacokinetic properties. The overall goal of this project is to select a Development Candidate for the treatment of COVID-19 and ready the compound for IND-enabling GLP toxicity studies.

项目概要 2019 年 SARS-CoV-2 的出现导致了急性呼吸道疾病的持续流行，缺乏治疗选择给世界医疗保健系统带来了压力，并导致超过 600 万人死亡。治疗冠状病毒感染也继续使人们面临新变种的严重风险作为未来人畜共患冠状病毒感染的加速药物发现/开发技术，包括药物。重新利用和快速追随药物设计仅导致单一口服生物可利用药物的批准 Nirmatrelvir/Paxlovid 对大部分患者是禁忌的，因为容易出现这种情况。因此，未来可能不会表现出抗性变体对未来冠状病毒威胁的交叉活性。应重点开发新的抗病毒药物，包括具有互补性的药物在第二阶段项目中，我们将执行一项药物研究。一系列新型 SARS-CoV-2 进入抑制剂的化学/分析策略和全面优化提高其针对 SARS-CoV-2 和其他冠状病毒的抗病毒活性及其药代动力学该项目的总体目标是选择治疗 COVID-19 的开发候选药物。并准备好该化合物用于支持 IND 的 GLP 毒性研究。