Design, synthesis and biological evaluation of novel, orally bioavailable pyrimidine-fused heterocycles as influenza PB2 inhibitors.


School of Pharmacy, Fudan University, Shanghai, 201203, PR China. Electronic address: [Email]


With the aim to identify novel influenza PB2 inhibitors with high potency and excellent pharmacokinetic parameters, we have designed and synthesized two new series of pyrimidine-fused heterocycle derivatives based on two generations of co-crystal structures. Docking studies with the newly disclosed PDB structure guided the second round of rational design and led to the discovery of 25m, 25o and 25p as representative compounds with improved potency (EC50 < 1 nM). After pinpointing the metabolic labile site, the CN replacement of compound 25p successfully produced compound 29c, which demonstrated highly improved PK properties (Cl = 1.3 mL/min/kg, PO AUC = 152 μM h at 10 mpk in mouse, F = 57%) and improved potency, emerging as a promising lead compound for the treatment of influenza A infection.


Drug design,Influenza,Metabolic stability,PB2,Polymerase inhibitor,