Discovery of Tricyclic Derivative as Novel and Potent Respiratory Syncytial Virus Fusion Glycoprotein Inhibitor with an Improved Pharmacokinetic Profile

Respiratory syncytial virus (RSV) is a major pathogen
causing acute
respiratory infections, and the RSV fusion glycoprotein (F) has been
identified as a key target for developing small-molecule inhibitors.
Based on our prior identification of lonafarnib as an F protein inhibitor,
medicinal chemistry efforts led to the development of CGR-51, which exhibits significantly enhanced potency against both laboratory
and clinical RSV isolates in cellular assays. Time-of-addition and
SPR assays indicate that CGR-51 inhibits viral entry
by targeting the RSV F protein, but has farnesyltransferase-independent
antiviral efficacy. Passage of RSV with CGR-51 selects
for phenotypic resistance with the emergence of the K399N mutation
in the RSV F protein. Additionally, CGR-51 exhibits an
improved pharmacokinetic profile and effectively suppresses RSV replication
in a BALB/c mouse model of RSV infection, while showing lower toxicity
compared to lonafarnib. Collectively, CGR-51 represents
a promising RSV F protein inhibitor candidate for the treatment of
RSV infection.