Chemistry: molecular biology and microbiology – Micro-organism – per se ; compositions thereof; proces of... – Bacteria or actinomycetales; media therefor
Reexamination Certificate
1999-06-23
2001-10-02
Ware, Deborah K. (Department: 1651)
Chemistry: molecular biology and microbiology
Micro-organism, per se ; compositions thereof; proces of...
Bacteria or actinomycetales; media therefor
C424S093430, C435S041000, C435S052000, C435S170000, C435S183000, C435S252100, C435S822000, C435S886000
Reexamination Certificate
active
06297043
ABSTRACT:
The present invention relates to a compound named Mumbaistatin which is obtainable by cultivation of the microorganism HIL-008003 (DSM 11641), and to its pharmaceutically acceptable salts and derivatives. Mumbaistatin is a glucose-6-phosphate translocase inhibitor and can be used in the treatment of diabetes mellitus. The present invention further relates to a process for the production of Mumbaistatin, to the microorganism HIL-008003 (DSM 11641), to the use of Mumbaistatin and its pharmaceutically acceptable salts and derivatives as pharmaceuticals, in particular for their use in the treatment of diabetes mellitus, and to pharmaceutical compositions comprising Mumbaistatin or a pharmaceutically acceptable salt or derivative thereof.
Increased rate of hepatic glucose output is a general feature of diabetes mellitus. In particular, there is a strong correlation between fasting plasma glucose level in non-insulin dependent diabetes mellitus (NIDDM) and hepatic glucose output. The two pathways by which glucose is produced in the liver are gluconeogenesis and glycogenolysis. The terminal steps of both pathways are catalyzed by the microsomal glucose-6-phosphatase, a key enzyme in the homeostatic regulation of blood glucose levels. The level of this enzyme has also been known to be elevated in both experimental and pathological conditions of diabetes. Interference with this enzyme system should, therefore, result in a reduced hepatic glucose production.
Hepatic glucose-6-phosphatase is a multicomponent system comprised of at least three functional activities: a glucose-6-phosphate translocase (T1), a glucose-6-phosphate phosphohydrolase and a phosphate/pyrophosphate translocase (T2). The glucose-6-phosphate translocase facilitates transport of glucose-6-phosphate into the lumen of the endoplasmic reticulum (ER). The phosphohydrolase, with its active site situated on the lumenal surface of the ER, hydrolyses glucose-6-phosphate and releases glucose and phosphate into the lumen. While the efflux of phosphate is facilitated by the phosphate/pyrophosphate translocase, the exact mechanism of glucose efflux is still not clear.
The high degree of substrate specificity of glucose-6-phosphate translocase makes this a potential target for pharmacological intervention in the treatment of diabetes mellitus. Thus, amongst physiologically occurring sugar phosphates, only glucose-6-phosphate is transported by the translocase. In contrast, the phosphatase is non-specific and is known to hydrolyze a variety of organic phosphate esters.
A series of non-specific inhibitors of glucose-6-phosphatase has been described in the literature, e.g. phlorrhizin (
J. Biol. Chem.
242, 1955-1960 (1967)), 5,5′-dithio-bis-2-nitrobenzoic acid (
Biochem. Biophys. Res. Commun.
48, 694-699 (1972)), 2,2′-diisothiocyanatostilbene and 2-isothiocyanato-2′-acetoxystilbene (
J. Biol. Chem.
255, 1113-1119 (1980)). The first therapeutically utilizable inhibitors of the glucose-6-phosphatase system are proposed in European patent applications EP-A-587 087 and EP-A-587 088. Kodaistatins A, B, C, and D described in international patent application no. PCT/EP 98/02247 are the first glucose-6-phosphate translocase inhibitors from microbial sources.
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Deshmukh Sunil Kumar
Kogler Herbert
Kota Sridevi
Kumar Erra Koteswara Satya Vijaya
Kurz Michael
Aventis Pharma Deutschland GmbH
Finnegan, Henderson Farabow, Garrett and Dunner L.L.P.
Ware Deborah K.
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