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

Affiliation

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

Cat. No.

Product Name

Description

Target

Research Area
HY-16727

Presatovir

99.91%, RSV Fusion Inhibitor

RSV

Infection

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