Eisai R&d Management Co., Ltd.

Eisai Company, Limited

Kazutaka Nakamoto

Keigo Tanaka

Itaru Tsukada

Katsura Hata

Kappei Tsukahara

Koji Sagane

Norihiro Ueda

Naoaki Watanabe

Satoshi Inoue

Masayuki Matsukura

Mamiko Tsuchiya

Fuminori Ohba

Junko Kai

Shinya Abe

Norio Murai

Shuji Shirotori

Toru Haneda

Kaoru Ogawa

Toshihiro Horii

Jun Niijima

Eiichi Yamamoto

Takuma Minamisono

An object of the present invention is to provide an antifungal agent which has excellent antifungal effects and is superior in terms of its physical properties, safety and metabolic stability. According to the present invention, there is disclosed a compound represented by the following formula (I), or a salt thereof: wherein R, R, X, Y, ring A, Z, Rand Rare as defined in the specification.

Heterocycles substituted pyridine derivatives and antifungal agent containing thereof

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

An object of the present invention is to provide an antifungal agent which has excellent antifungal effects and is superior in terms of its physical properties, safety and metabolic stability. According to the present invention, there is disclosed a compound represented by the following formula (I), or a salt thereof: wherein Rrepresents a hydrogen atom, a halogen atom, an amino group, a Calkyl group, a Calkoxy group or a Calkoxy Calkyl group; Rrepresents a hydrogen atom, a Calkyl group, an amino group or a di Calkylamino group; one of X and Y is a nitrogen atom while the other is a nitrogen atom or an oxygen atom; ring A represents a 5- or 6-member heteroaryl ring or a benzene ring which may have a halogen atom, or 1 or 2 Calkyl groups; Z represents a single bond, a methylene group, an ethylene group, an oxygen atom, a sulfur atom, &#x2014;CHO&#x2014;, &#x2014;OCH&#x2014;, &#x2014;NH&#x2014;, &#x2014;CHNH&#x2014;, &#x2014;NHCH&#x2014;, &#x2014;CHS&#x2014;, or &#x2014;SCH&#x2014;; Rrepresents a hydrogen atom, a halogen atom, a Calkyl group, a Ccycloalkyl group, a Caryl group, a 5- or 6-member heteroaryl group, or 5- or 6-member non-aromatic heterocyclic group which may have 1 or 2 substituents; and Rrepresents a hydrogen atom or a halogen atom.

There is provided a heterocycle-substituted pyridine derivative's salt or a crystal thereof. The present invention provides an acid addition salt of 3-(3-(4-(pyridin-2-yloxymethyl)-benzyl)-isoxazol-5-yl)-pyridin-2-yl amine or a crystal thereof as well as process for producing the same.

Heterocycle-substituted pyridine derivative's salt or crystal thereof

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.

The present invention provides an antifungal agent that has superior antifungal action and is also superior in terms of physical properties, safety and metabolic stability. The present invention discloses a compound represented by the formula (I): (wherein X represents an oxygen atom, a sulfur atom or &#x2014;NH&#x2014;, Rrepresents a hydrogen atom, a halogen atom, a cyano group, an amino group or a substituent, and Rand Rindependently represent a hydrogen atom, a halogen atom, a hydroxyl group or a substituent, except for a case in which Rand Rare both hydrogen atoms), and an antifungal agent containing the above compound.

Growing community of inventors

Tsukuba, Japan

Kazutaka Nakamoto