{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"omics_type":["Unknown"],"submitter":["Jaishankar P"],"funding":["NIAID NIH HHS","NIGMS NIH HHS"],"pubmed_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 (<b>1</b>), a potent and selective inhibitor of the SARS-CoV-2 ADP-ribosylhydrolase Mac1 based on a 9<i>H</i>-pyrimido[4,5-<i>b</i>]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 <b>1</b> and many of its analogs. Multiple strategies were pursued to overcome these issues, including replacing a ur"],"journal":["bioRxiv : the preprint server for biology"],"pagination":["2025.10.11.681833"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC12632963"],"repository":["biostudies-literature"],"pubmed_title":["Discovery of AVI-6451, a Potent and Selective Inhibitor of the SARS-CoV-2 ADP-Ribosylhydrolase Mac1 with Oral Efficacy in vivo."],"pmcid":["PMC12632963"],"funding_grant_id":["P30 GM133894","U19 AI171110","P30 GM124169"],"pubmed_authors":["Rachman MM","Correy GJ","Krogan NJ","Jaishankar P","Montano M","Fraser JS","Renslo AR","Taha TY","Shoichet BK","Zheng J","Pampel J","Stevens MGV","Hantz ER","Ashworth A","Ott M","Matsui Y","Togo T","Rosecrans J","Diolaiti ME"],"additional_accession":[]},"is_claimable":false,"name":"Discovery of AVI-6451, a Potent and Selective Inhibitor of the SARS-CoV-2 ADP-Ribosylhydrolase Mac1 with Oral Efficacy in vivo.","description":"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 (<b>1</b>), a potent and selective inhibitor of the SARS-CoV-2 ADP-ribosylhydrolase Mac1 based on a 9<i>H</i>-pyrimido[4,5-<i>b</i>]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 <b>1</b> and many of its analogs. Multiple strategies were pursued to overcome these issues, including replacing a ur","dates":{"release":"2025-01-01T00:00:00Z","publication":"2025 Oct","modification":"2026-06-04T03:16:02.101Z","creation":"2026-06-04T03:11:17.733Z"},"accession":"S-EPMC12632963","cross_references":{"pubmed":["41279160"],"doi":["10.1101/2025.10.11.681833"]}}