Cu. Kim, Rational drug design of orally active influenza neuraminidase inhibitors: Discovery and development of GS 4104, MED CHEM RE, 8(7-8), 1998, pp. 392-399
The design, synthesis and in vitro evaluation of the novel carbocycles as t
ransition-state based inhibitors of influenza neuraminidase (NB) are descri
bed. The presence of a large hydrophobic pocket in the region corresponding
to the glycerol subsite of sialic acid was exploited to optimize the hydro
phobic interaction with alkyl chains of the carbocyclic analogues 7. Extens
ive structure-activity relationship studies have identified compound 8 (GS
4071) as one of the most potent influenza NA inhibitors in this series with
an IC50 Of 1 nM. Currently, the ethyl ester prodrug 9 (GS 4104) is being e
valuated for the oral treatment and prophylaxis of influenza infection in P
hase II/III clinical studies.