Development of 4-(aroylamino)piperidine-based entry inhibitors as anti-influenza therapeutics

Influenza A viruses belong to the orthomyxoviridae family, and have a negative-sense, segmented RNA
genome, which can cause seasonal or pandemic flu with high morbidity and significant mortality.
Vaccination is the most prevalent prophylactic means for controlling influenza infections. However, an
effective vaccine usually takes at least six months to develop. Furthermore, vaccination has limited
effectiveness in the treatment of immunocompromised patients, and its effectiveness is also limited
during a pandemic. The current therapeutic options for flu infections are all based on the neuraminidase
inhibitors (NAIs; oseltamivir, zanamivir and peramivir), while the influenza M2 ion channel blockers
(amantadine and rimantadine) are not now recommended since all of the circulating influenza strains
have acquired resistance. (Xofluza, a polymerase acidic endonuclease inhibitor, has just been approved
in 2018 and is yet untried during a flu season.) The rapid emergence of the NAI-resistant strains of
influenza A viruses strongly suggests that NAIs alone may not be sufficient as effective therapies, and
thus new treatment options targeting the other viral/host factors are urgently needed. This application
defines a plan to develop potent, small molecule inhibitors, which block entry of influenza A viruses. We
have identified compounds that inhibit entry of infectious influenza A viruses, with IC50 values in the
nanomolar range. We have synthesized structurally diverse analogs of the anti-influenza hit series using
structure-activity relationships (SARs) to improve potency and selectivity; validated the lead inhibitor
candidates in the infectious assay and investigated the mechanism of action (MOA) of the these
inhibitors; and selected anti-influenza inhibitors with excellent in vitro potency and selectivity values and
druglike in vivo pharmacokinetic properties. In this Fast Track STTR Phase I andamp;II application, we propose
four specific aims: (1) optimize the lead scaffold and select development candidates; (2) investigate the
mechanism of action (MOA) of the advanced lead compounds with HA proteins; (3) evaluate the
pharmacokinetics/toxicokinetics of the advanced lead compounds; and (4) preclinical development.Project Narrative
This project is to discover and develop small molecule entry inhibitors for influenza viral
infection. The proposed research will help to develop potential antiviral therapeutics.