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Discovery of an oral respiratory syncytial virus (RSV) fusion inhibitor (GS-5806) and clinical proof of concept in a human RSV challenge study. 2015
Richard L Mackman, and
Michael Sangi, and
David Sperandio, and
Jay P Parrish, and
Eugene Eisenberg, and
Michel Perron, and
Hon Hui, and
Lijun Zhang, and
Dustin Siegel, and
Hai Yang, and
Oliver Saunders, and
Constantine Boojamra, and
Gary Lee, and
Dharmaraj Samuel, and
Kerim Babaoglu, and
Anne Carey, and
Brian E Gilbert, and
Pedro A Piedra, and
Robert Strickley, and
Quynh Iwata, and
Jaclyn Hayes, and
Kirsten Stray, and
April Kinkade, and
Dorothy Theodore, and
Robert Jordan, and
Manoj Desai, and
Tomas Cihlar
Gilead Sciences , 333 Lakeside Drive, Foster City, California 94404, United States.
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.
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