| Literature DB >> 25574686 |
Richard L Mackman1, 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.
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.Entities:
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Year: 2015 PMID： 25574686 DOI： 10.1021/jm5017768
Source DB: PubMed Journal: J Med Chem ISSN： 0022-2623 Impact factor: 7.446