Rational drug design of orally active influenza neuraminidase inhibitors: Discovery and development of GS 4104

Authors
Citation
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
Citations number
13
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Chemistry & Analysis
Journal title
MEDICINAL CHEMISTRY RESEARCH
ISSN journal
1054-2523 → ACNP
Volume
8
Issue
7-8
Year of publication
1998
Pages
392 - 399
Database
ISI
SICI code
1054-2523(1998)8:7-8<392:RDDOOA>2.0.ZU;2-9
Abstract
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.