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.

项目摘要 SARS-COV-2在2019年的出现导致急性呼吸道疾病的流行病，已经强调了世界医疗保健系统，并导致600万人死亡。缺乏治疗选择治疗冠状病毒感染也继续暴露于新兴变种中的严重风险作为未来的人畜共努性冠状病毒感染。加速药物发现/开发技术，包括药物重新利用和快速的追随者药物设计仅导致单一口服可生物可利用的批准抑制剂。 Nirmatrelvir/paxlovid在很大一部分患者中禁忌，容易出现抵抗变体，可能不会表现出对未来冠状病毒威胁的跨活动。因此，未来努力应着重于开发新抗病毒药，包括拥有完整的抗病毒药作用和阻力剖面的机制。在此阶段2项目中，我们将执行医疗化学/分析策略和一系列新型SARS-COV-2进入抑制剂的完整优化改善对SARS-COV-2和其他冠状病毒的抗病毒活性以及药代动力学特性。该项目的总体目标是选择一个候选候选人的竞争者-19 并准备好的化合物以辅助GLP毒性研究。