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

项目总结 2019年SARS-CoV-2的出现导致了一种持续的急性呼吸道疾病疫情， 给世界卫生保健系统带来压力，并导致600万人死亡。缺乏治疗的选择 治疗冠状病毒感染继续使人群面临新出现变种的严重风险 作为未来的人畜共患冠状病毒感染。加速药物发现/开发技术，包括药物 重新调整用途和快速跟进的药物设计只批准了一种口服生物利用度 抑制剂。Nirmatrelvir/Paxlovid在很大一部分患者中是禁忌，容易出现 抗药性变异体，可能不会对未来的冠状病毒威胁表现出交叉活性。因此，未来 努力应侧重于开发新的抗病毒药物，包括那些具有互补性的抗病毒药物。 作用机制和抗药性概况。在这个二期项目中，我们将执行一项医疗 一系列新型SARS-CoV-2进入抑制剂的化学/图谱策略和完全优化 提高其抗SARS-CoV-2等冠状病毒的活性和药代动力学 属性。该项目的总体目标是为新冠肺炎的治疗选择一个发展候选者 并为支持IND的GLP毒性研究准备化合物。

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.