Abstract

Small molecule inhibition of viral proteases has been a successful anti-viral therapeutic strategy in HIV and HCV . Structural insight on the SARS -CoV-2 main protease (Mpro) and previous small molecule experience with intravenous SARS -CoV-1 inhibitors gave a starting point for an oral Mpro inhibitor program in response to the COVID -19 outbreak. Designing and synthesizing molecules in a peptidomimetic chemotype, the team investigated a number of cysteine traps as reversibly covalent inhibitors, while looking to confer sufficient metabolic stability and permeability to attain oral bioavailability. Systematically challenging the need for hydrogen bond donors throughout the pharmacophore proved a successful strategy for enhancing permeability. This resulted in the discovery of PF-7321332, the first oral SARS -CoV-2 Mpro inhibitor to reach clinical development.1

PF-7321332 showed pan-human coronavirus activity with selectivity over human proteases. Phase 1 healthy volunteer studies will be described, with and without combination of low dose ritonavir as a pharmacokinetic enhancer. The preclinical work to identify PF-7321332 (now known as nirmatrelvir) and the resulting Ph1 study was the basis for a combined Ph2/3 study in high-risk patients. Nirmatrelvir/ritonavir went on to receive emergency use authorization for the treatment of high risk COVID -19 patients in the United States as PAXLOVID in December of 2021, just 17 months after nirmatrelvir was first synthesized and received full FDA approval in May 2023.

The ‘start to finish’ drug discovery story will be presented from a medicinal chemist’s point of view.