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

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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.