1 research outputs found
Discovery of an Oral Respiratory Syncytial Virus (RSV) Fusion Inhibitor (GS-5806) and Clinical Proof of Concept in a Human RSV Challenge Study
GS-5806
is a novel, orally bioavailable RSV fusion inhibitor discovered
following a lead optimization campaign on a screening hit. The oral
absorption properties were optimized by converting to the pyrazolo[1,5-<i>a</i>]-pyrimidine heterocycle, while potency, metabolic, and
physicochemical properties were optimized by introducing the <i>para</i>-chloro and aminopyrrolidine groups. A mean EC<sub>50</sub> = 0.43 nM was found toward a panel of 75 RSV A and B clinical isolates
and dose-dependent antiviral efficacy in the cotton rat model of RSV
infection. Oral bioavailability in preclinical species ranged from
46 to 100%, with evidence of efficient penetration into lung tissue.
In healthy human volunteers experimentally infected with RSV, a potent
antiviral effect was observed with a mean 4.2 log<sub>10</sub> reduction
in peak viral load and a significant reduction in disease severity
compared to placebo. In conclusion, a potent, once daily, oral RSV
fusion inhibitor with the potential to treat RSV infection in infants
and adults is reported