Eisai R&d Management Co., Ltd.

Eisai Company, Limited

Katsura Hata

Itaru Tsukada

Keigo Tanaka

Kazutaka Nakamoto

Kappei Tsukahara

Koji Sagane

Norihiro Ueda

Naoaki Watanabe

Mamiko Tsuchiya

Fuminori Ohba

Junko Kai

Akihiko Tsuruoka

Kazumasa Nara

Toshihiko Naito

Toshio Toyosawa

Manabu Yanagisawa

Yumiko Kaku

Kaoru Ogawa

Toshihiro Horii

Shinya Abe

Satoshi Inoue

Masayuki Matsukura

Toru Haneda

Hiroshi Ishihara

Geoff Hird

Hiroki Muto

A formulation comprising liposomes, wherein the liposomes comprise, based on the liposome, 0.7 to 3.0 mol % of eritoran or a pharmaceutically acceptable salt thereof and 0.5 to 3.0 mol % of a PEGylated phospholipid.

Formulation comprising liposomes

The present inventors succeeded in isolating GWT1 (PfGWT1), which is one of the enzymes involved in GPI biosynthesis in the malaria parasite. In addition, the inventors revealed that degenerate mutant DNAs, with a lower AT content than the DNA encoding the PfGWT1 protein, can complement the phenotype of GWT1-deficient yeast. Based on the findings, the present invention provides the GWT1 protein of malaria parasites and the use of the protein in methods of screening for antimalarial drugs. The present invention also provides degenerate mutant DNAs encoding proteins involved in GPI biosynthesis, and which have a lower AT content than the original DNAs. The present invention also provides methods of screening for antimalarial drugs which use the degenerate mutant DNAs.

Methods of screening for compounds that inhibit the biosynthesis of GPI in malaria parasites

The present invention provides isolated DNA encoding a GWT1 protein having activity to confer resistance of a fungus against a compound of formula Ia, and wherein a defect of a function of the GWT1 protein leads to a decrease in the amount of a glycosylphosphatidylinositol (GPI)-anchored protein in the cell wall of a fungus.

Fungal cell wall synthesis gene

The present invention provides an antifungal agent represented by the formula: [wherein Arepresents a 3-pyridyl group which may have a substituent, a quinolyl group which may have a substituent, or the like; Xrepresents a group represented by the formula &#x2014;NH&#x2014;C(&#x2550;O)&#x2014;, a group represented by the formula &#x2014;C(&#x2550;O)&#x2014;NH&#x2014;, or the like; E represents a furyl group, a thienyl group, a pyrrolyl group, a phenyl group, a pyridyl group, a tetrazolyl group, a thiazolyl group or a pyrazolyl group; with the proviso that Amay have 1 to 3 substituents, and E has one or two substituents].

Antifungal agent containing heterocyclic compound

A reporter system reflecting the transport process that transports GPI-anchored proteins to the cell wall was constructed and compounds inhibiting this process were discovered. Further, fungal genes conferring resistance to the above compounds were identified and methods of screening for compounds that inhibit the activity of the proteins encoded by these genes were developed. These genes encode proteins participating in fungal cell wall synthesis. Therefore, through the novel compounds, the present invention showed that antifungal agents having a novel mechanism, i.e. inhibiting the process that transports GPI-anchored proteins to the cell wall, could be achieved.

A reporter system reflecting the transport process that transports GPI-anchored proteins to the cell wall was constructed and compounds inhibiting this process were discovered. Further, genes conferring resistance to the above compounds were identified and methods of screening for compounds that inhibit the activity of the proteins encoded by these genes were developed. Therefore, through the novel compounds, the present invention showed that antifungal agents having a novel mechanism, i.e. inhibiting the process that transports GPI-anchored proteins to the cell wall, could be achieved.

A compound represented by the general formula: ##STR1## wherein R.sup.1 and R.sup.2 denote a halogen atom or hydrogen atom; R.sup.3 means a hydrogen atom or lower alkyl group; l, r and m stand for 0 or 1; A is N or CH; W denotes an aromatic ring or a condensed ring thereof; X means another aromatic ring, an alkanediyl group, an alkenediyl group, or an alkynediyl group; Y stand for --S--, etc.; Z denotes a hydrogen atom, etc., or a salt thereof, and intermediates thereof or a salt thereof as well as processes for the preparation thereof, and pharmaceutical composition suitable for use as an antifungal agent.

Antifungal agents, processes for the preparation thereof, and

A compound represented by the general formula: ##STR1## wherein R.sup.1 and R.sup.2 denote a halogen atom or hydrogen atom; R.sup.3 means a hydrogen atom or lower alkyl group; l, r and m stand for 0 or 1; A is N or CH; W denotes an aromatic ring or a condensed ring thereof; X means another aromatic ring, an alkanediyl group, an alkenediyl group, or an alkynediyl group; Y stand for --S--, etc.; Z denotes a hydrogen atom, etc., or a salt thereof, and intermediates thereof or a salt thereof as well as processes for the preparation thereof, and pharmacetical composition suitable for use as an antifungal agent.

Antifungal agents, and compositions

Growing community of inventors

Tsukuba, Japan

Katsura Hata