Inhibition of fatty acid synthase as a means to reduce adipocyte

Details Inhibition of fatty acid synthase as a means to reduce adipocyte Inhibition of fatty acid synthase as a means to reduce adipocyte

1998-01-27

1999-11-09

Reamer, James H.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

A01K 3104

Patent

active

059815752

DESCRIPTION:

BRIEF SUMMARY
BACKGROUND OF THE INVENTION

1. Field of the Invention
This invention concerns the systemic administration of an inhibitor of fatty acid synthase (E.C. 2.3.1.85, FAS) by any suitable route to achieve weight loss and/or reduction of adipocyte mass without significant toxicity. Use of FAS inhibitors for this purpose is not restricted to humans or any species, but includes reduction of adipocyte mass in livestock and poultry. This invention also concerns the synthesis of a family of compounds (.alpha.-methylene-.beta.-carboxy-.gamma.-butyrolactones) which are fatty acid synthesis inhibitors, and the use of these compounds to achieve weight loss, to treat susceptible cancer cells, or in other applications characteristic of FAS inhibitors.
2. Review of Related Art
Compounds and proteins which induce reduction of weight or adipocyte mass in mammals may act through the following mechanisms: [1] increased fat mobilization, such as human chorionic gonadotrophin (HCG) induced metabolism of fat stores (Bray, et al., "Nutritional Support of Medical Practice," Harper and Row, Philadelphia, 1983); [2] increased calorigenesis, such as that induced by thyroid hormone (Abraham et al., 1985, Int. J. Obes., 9:433-42); [3] decreased appetite, induced by anorexic agents such as felbamate and dexfenfluramine (McTavish et al., 1992, Drugs, 43:713-33); [4] decreased lipogenesis (see Table 1 below); and [5] mutated or decreased blood levels of the ob gene product (Halaas et al., 1995, Science, 269:543-546). In mice (Kannan et al., 1980, Lipids, 15:993-8) and man, significant fatty acid synthesis occurs in liver (Triscari et al., 1985, Metabolism, 34:580-7; Barakat et al., 1991, Metabolism, 40:280-5) and adipose tissue (Goldrick et al., 1974, Clin. Sci. Mol. Med., 46:469-79), and rates of fatty acid synthesis are higher in obese mice or humans (Angel et al., 1979, Eur. J. Clin. Invest., 9:355-62; Belfiore et al., 1976, Metabolism, 25:483-93). Hence, it is not surprising that a number of weight reducing agents reduce de novo fatty acid synthesis. Table 1 provides a list of agents known to both inhibit lipogenesis and induce weight loss.


TABLE 1 ______________________________________ Compounds Which Induce Weight Loss ENZYME TARGET and REFERENCES and COMPOUND TYPE OF INHIBITION SPECIES STUDIED ______________________________________ TPIA & CPIB acetyl-CoA carboxylase, Maragoudakis, 1969, mixed competitive and J. Biol. Chem, 244: (non-competitive) 5005-13 (rodent study) Sodium 2-n-penta- acetyl-CoA carboxylase, Whittington et al., decylbenzimidazole-5- (competitive (?)) 1987, Int. J. Obes., 11: carboxylate 619-29 (rodent study) Dehydroepiando- glucose-6-phosphate Yen et al., 1981, sterone dehydrogenase, Lipids, 12: 409-13 (competitive) (rodent study) (-) hydroxycitrate ATP citrate lyase, Greenwood et al., (competitive) 1981, Am. J. Physiol., 240: E72-8. (rodent study) 30 kD protein enzyme target unknown, Harris, et al., 1989, inhibits FA synthesis Am. J. Physiol., 257: R326-36 (rodent study) ob gene product protein produced by Halaas et al., 1995, adipocytes which inhibits Sciences, 269: 543-6 appetite (rodent study) ______________________________________ Interestingly, no inhibitors of fatty acid synthase (FAS) (E.C. 2.3.1.85) are mentioned in prior art as agents which produce weight loss.


SUMMARY OF THE INVENTION

It is an object of this invention to provide a method for inducing weight reduction focused on a new therapeutic target.
It is a further object of this invention to provide novel compounds that inhibit the activity of FAS; in particular, compounds with increased bioavailability and very low toxicity, compared to previously available FAS inhibitory compounds.
This invention provides a method for inducing weight loss in an animal comprising administering to the animal a compound which reduces fatty acid synthase (FAS) activity in adipocytes or liver cells, the compound being other than a fat or a metabolizable product of a fat (i.e., the compound does not inhibi

REFERENCES:
patent: 3535309 (1970-10-01), Hata et al.
patent: 3630846 (1971-12-01), Hata et al.
patent: 3897428 (1975-07-01), Omura et al.
patent: 3909361 (1975-09-01), Hata et al.
patent: 4000164 (1976-12-01), Parker
patent: 4011334 (1977-03-01), Parker
patent: 4032647 (1977-06-01), Parker
patent: 4110351 (1978-08-01), Parker
patent: 4146623 (1979-03-01), Parker
patent: 4328246 (1982-05-01), Gold
patent: 4602099 (1986-07-01), Parker
patent: 4738984 (1988-04-01), Parker
patent: 4789630 (1988-12-01), Bloch et al.
patent: 4968494 (1990-11-01), Claremon et al.
patent: 5032611 (1991-07-01), Taguchi et al.
patent: 5143907 (1992-09-01), Spielvogel
patent: 5185149 (1993-02-01), Baldwin et al.
patent: 5188830 (1993-02-01), Atkinson et al.
patent: 5190969 (1993-03-01), Blumenstein et al.
patent: 5246960 (1993-09-01), Barbier et al.
patent: 5614551 (1997-03-01), Dick et al.
patent: 5759836 (1998-06-01), Kuhajda et al.
Bacchi, et al., "Effects of Some Antitumor Agents on Growth and Glycolytic Enzymes of the Flagellate Crithidia," J. Bacteriol., 98:23-28 (1969).
Furnica, et al., "Mecanismes Biochimiques Impliques Dans La Sensibilisation Des Organismes Vivants Par Des Agents Chimiques A L'Action Des Radiations et Des Cytostatiques," Rev. Roum. Biochim., 8:117-122 (1971).
Omura, et al., "Relationship Between the Structures of Fatty Acid Amide Derivatives and Their Antimicrobial Activities," Antimicrobial Agents and Chemotherapy, 6:207-215 (1974).
Omura, Satoshi, "The Antibiotic Cerulenin, a Novel Tool for Biochemistry as an Inhibitor of Fatty Acid Synthesis," Bacteriological Reviews, 40:681-697 (1976).
Altenbern, Robert A., "Cerulenin-Inhibited Cells of Staphylococcus aureus Resume Growth When Supplemented with Either a Saturated or an Unsaturated Fatty Acid," Antimicrobial Agents and Chemotherapy, 11:574-576 (1977).
Altenbern, Robert A., "Extreme Sensitivity of Staphylococcal Enterotoxin B and C Production to Inhibition by Cerulenin," Antimicrobial Agents and Chemotherapy, 11:906-908 (1977).
Partida, et al., "Comparative Effects of Diphenylglioxal and its Superoxide on Experimental Tumors," Arch. de Farmacol. y Toxicol., III:231-240 (1977).
Chen, et al., "The Cerulenin-Induced Formation of 1-Acyl-Lysophosphatidyl Glycerol in Bacillus megaterium," Biochem. Biophys. Res. Comm., 80:126-132 (1978).
Carson, et al., "Effect of Cerulenin on Streptococcus faecalis Macromolecular Synthesis and Cell Division," J. Bacteriol., 133:472-476 (1978).
Caulfield, et al., "Export of Extracellular Levansucrase by Bacillus subtilis: Inhibition by Cerulenin and Quinacrine," J. Bacteriol., 138:345-351 (1979).
Leung, et al., "Streptococcus mutans Dextransucrase: Effect of Cerulenin on Lipid Synthesis and Enzyme Production," Infection and Immunity, 28:846-852 (1980).
Smith, et al., "Thioesterase II, a New Marker Enzyme for Human Cells of Breast Epithelial Origin," JNCI, 73:323-329 (1981).
Carson, et al., "Effect of Cerulenin on Cellular Autolytic Activity and Lipid Metabolism During Inhibition of Protein Synthesis of Streptococcus faecalis," J. Bacteriol., 146:590-604 (1981).
Bocquet-Pages, et al., "Lipid-Synthesis-Dependent Biosynthesis (or Assembly) of Major Outer-Membrane Proteins of Escherichia coli," Eur. J. Biochem., 118:105-111 (1981).
Omura, Satoshi, Chapter 39 "Cerulenin" in Methods in Enzymology, 72:520-532 (1981).
Thompson, et al., "Purification and Properties Of Fatty Acid Synthetase From A Human Breast Line," Biochim. Biophys. Acta, 662:125-130 (1981).
Ahmad, et al., "Studies on Acetyl-CoA Carboxylase and Fatty Acid Synthase from Rat Mammary Gland and Mammary Tumors," Biochem. J., 208:443-452 (1982).
Clements, et al., "Irreversible Inhibition of Fatty Acid Synthase from Rat Mammary Gland with S-(4-bromo-2,3-dioxobutyl)-CoA," Biochem. J., 207:291-296 (1982).
Thompson, et al., "Lack of Coordinated Regulation Of Lipogenic Enzymes In A Human Breast Cell Line SKBr3," Biochim. Biophys. Acta, 712:217-220 (1982).
Mantsala, et al., "Secretion of .beta.-lactamase by Escherichia coli in vivo

Affiliated with

Also associated with

Rating

Inhibition of fatty acid synthase as a means to reduce adipocyte does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Inhibition of fatty acid synthase as a means to reduce adipocyte, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Inhibition of fatty acid synthase as a means to reduce adipocyte will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-1456664