The SARS-CoV-2 3C-like protease (3CLpro) inhibitor PF-07321332 (nirmatrelvir), in combination with ritonavir (PaxlovidTM) was recently granted emergency use authorization by multiple regulatory agencies across the globe including the United States Food and Drug Administration for the treatment of mild-to-moderate COVID-19 in adults and pediatric patients (12 years of age and older), who are at high risk for progression to severe COVID-19, including hospitalization or death. The presentation will dwell into the discovery ADME strategies that were adopted for bespoke SARS-CoV-2 3CLpro inhibitor designs that seeked to improve the poor oral absorption characteristics of the previously identified SARS-CoV-1 3CLpro clinical candidate PF-00835231. While a reduction in hydrogen bond donor count, which was thought to be the principal cause for the poor oral absorption of PF-00835231, ultimately proved to be the winning medicinal chemistry strategy, alternate approaches such as prodrug analogs of PF-00835231 were also evaluated. The presentation will also discuss details of the cytochrome P450 reaction phenotyping studies that established a predominant role for CYP3A4 in nirmatrelvir metabolism, and proved useful in designing clinical studies involving co-administration of nirmatrelvir with the CYP3A4 inhibitor ritonavir. Finally, a de novo approach that examined human mass balance and disposition of Paxlovid using 19F-NMR spectroscopy (instead of the traditional 14C human ADME) will be outlined. The 19F NMR approach in studying mass balance/disposition has been accepted by regulatory agencies worldwide, and enabled the timely approval of the emergency use authorization.

ADME approaches for the Pfizer oral COVID-19 protease inhibitor program

Fall 2022 abstracts, posters, and presentations will launch in mid-September.

ACS Fall 2022

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.