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ID: ALA4334467

Journal: J Med Chem

Title: Synthesis and SAR Study of Carbamoyl Pyridone Bicycle Derivatives as Potent Inhibitors of Influenza Cap-dependent Endonuclease.

Authors: Miyagawa M, Akiyama T, Taoda Y, Takaya K, Takahashi-Kageyama C, Tomita K, Yasuo K, Hattori K, Shano S, Yoshida R, Shishido T, Yoshinaga T, Sato A, Kawai M.

Abstract: The medicinal chemistry and structure-activity relationships (SAR) for a novel series of carbamoyl pyridone bicycle (CAB) compounds as influenza Cap-dependent endonuclease (CEN) inhibitors are disclosed. Substituent effects were evaluated at the C (N)-1, N-3, and C-7 positions of the CAB ring system using a docking study. Submicromolar EC50 values were achieved in the cellular assay with C-7-unsubstituted CAB which possessed a benzhydryl group on either the C-1 or the N-1 position. An N-3 substituent was found to be critical for the plasma protein binding effect in vitro, and the CAB-N analogue 2v exhibited reasonable total clearance (CLtot). More importantly, compound 2v displayed significant efficacy in a mouse model infected with influenza viruses.

CiteXplore: 31386363

DOI: 10.1021/acs.jmedchem.9b00861