Discovery of an oral respiratory syncytial virus (RSV) fusion inhibitor (GS-5806) and clinical proof of concept in a human RSV challenge study

  • J Med Chem. 2015 Feb 26;58(4):1630-43. doi: 10.1021/jm5017768.
Richard L Mackman  1 ,  Michael Sangi ,  David Sperandio ,  Jay P Parrish ,  Eugene Eisenberg ,  Michel Perron ,  Hon Hui ,  Lijun Zhang ,  Dustin Siegel ,  Hai Yang ,  Oliver Saunders ,  Constantine Boojamra ,  Gary Lee ,  Dharmaraj Samuel ,  Kerim Babaoglu ,  Anne Carey ,  Brian E Gilbert ,  Pedro A Piedra ,  Robert Strickley ,  Quynh Iwata ,  Jaclyn Hayes ,  Kirsten Stray ,  April Kinkade ,  Dorothy Theodore ,  Robert Jordan ,  Manoj Desai ,  Tomas Cihlar
Affiliations
  • 1. Gilead Sciences , 333 Lakeside Drive, Foster City, California 94404, United States.
PMID: 25574686 DOI: 10.1021/jm5017768
Abstract

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-a]-pyrimidine heterocycle, while potency, metabolic, and physicochemical properties were optimized by introducing the para-chloro and aminopyrrolidine groups. A mean EC50 = 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 log10 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.

Products