Discovery of AVI-6451, a Potent and Selective Inhibitor of the SARS-CoV-2 ADP-Ribosylhydrolase Mac1 with Oral Efficacy in vivo.

ABSTRACT: The COVID-19 pandemic made plain the need for effective antivirals acting on novel antiviral targets, among which viral macrodomains have attracted considerable attention. We recently described AVI-4206 (1), a potent and selective inhibitor of the SARS-CoV-2 ADP-ribosylhydrolase Mac1 based on a 9H-pyrimido[4,5-b]indole core, the first Mac1 inhibitor to demonstrate antiviral efficacy in mouse models of SARS-CoV-2 infection, but requiring IP administration and frequent dosing. Herein we describe an extensive, structurally enabled medicinal chemistry effort to identify orally bioavailable Mac1 inhibitors by addressing permeability and efflux liabilities of 1 and many of its analogs. Multiple strategies were pursued to overcome these issues, including replacing a ur

SUBMITTER: Jaishankar P 

PROVIDER: S-EPMC12632963 | biostudies-literature | 2025 Oct

REPOSITORIES: biostudies-literature