WO2003066043A1 - Stimulation of cpt-1 as a means to reduce weight - Google Patents
Stimulation of cpt-1 as a means to reduce weight Download PDFInfo
- Publication number
- WO2003066043A1 WO2003066043A1 PCT/US2003/003839 US0303839W WO03066043A1 WO 2003066043 A1 WO2003066043 A1 WO 2003066043A1 US 0303839 W US0303839 W US 0303839W WO 03066043 A1 WO03066043 A1 WO 03066043A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- cpt
- activity
- fatty acid
- malonyl
- coa
- Prior art date
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- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
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- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
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- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
- C12Q1/48—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving transferase
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- G—PHYSICS
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- G01N2500/04—Screening involving studying the effect of compounds C directly on molecule A (e.g. C are potential ligands for a receptor A, or potential substrates for an enzyme A)
Definitions
- This invention is directed to a method for development of therapeutics that selectively enhance fatty acid oxidation, increase energy production, and reduce adiposity while preserving lean mass, through the pharmacological stimulation of CPT-1 activity.
- C75 Cerulenin treatment of MCF-7 human breast cancer cells in vitro significantly inhibits fatty acid oxidation, probably through increased levels of malonyl-CoA (Loftus, et al. (2000) Science, 288:2379-2381).
- C75 is a member of a family of ⁇ -methylene- ⁇ -butyrolactones which are known inhibitors of fatty acid synthase (FAS) (Kuhajda, et al. (2000) Proc. Natl. Acad Sci USA, 97:3450-3454).
- FAS fatty acid synthase
- C75 reduces the expression of hypothalamic neuropeptide-Y (NPY) leading to reversible inanition (Loftus, et al, 2000).
- NPY hypothalamic neuropeptide-Y
- NPY hypothalamic neuropeptide-Y
- ob/ob mice there was profound loss of fat in the liver and peripheral tissues despite the increased levels of hepatic malonyl-CoA (Loftus, et al., 2000).
- Malonyl-CoA is a potent inhibitor of fatty acid oxidation through its action as an inhibitor of carnitine-palmitoyl-transferase-1 (CPT-1) (Witters, et al. (1992) J. Biol. Chem., 267:2864-2867).
- CPT-1 enables the entry of long-chain acyl-CoA's into the mitochondria for fatty acid oxidation.
- FAS inhibitors genetically and diet-induced obese mice undergo a selective and significant loss of adipose tissue despite the high levels of malonyl-CoA induced by FAS inhibition.
- malonyl-CoA is a potent inhibitor of fatty acid oxidation through its inhibition of carnitine p almitoyltransferase-1 (CPT-1, E .C. 2.3.1.21), the rapid and s elective loss of adipose tissue was surprising. High systemic levels of malonyl-CoA would be expected to inhibit fatty acid oxidation leading instead to a selective loss of lean mass during C75 induced inanition.
- this invention provides a method of inducing weight loss comprising administering an agent that stimulates carnitine palmitoyl transferase — 1 (CPT-1) activity to the patient in need, including human p atients.
- CPT-1 carnitine palmitoyl transferase — 1
- the agent is administered in an amount sufficient to increase fatty acid oxidation.
- the agent is administered in an amount sufficient to antagonize malonyl Co A inhibition of CPT-1.
- the agent is administered in an amount sufficient to increase malonyl CoA level.
- malonyl CoA level is not substantially increased.
- Substantial increase in malonyl CoA level as contemplated herein is equivalent to about one-half the K; for malonyl CoA inhibition of CPT-1.
- the agent which stimulates CPT-1 activity also inhibits fatty acid synthase (FAS).
- FAS fatty acid synthase
- FAS is not significantly inhibited. Insignificant inhibition as contemplated herein is less that 15%, preferably less than 10%, and more preferably less than 5% inhibition.
- Methods for assay of FAS activity are disclosed in U.S. Patent No. 5,981,575, incorporated herein by reference.
- the agent which stimulates CPT-1 activity is not a compound of formula:
- R is a substitute selected from the group consisting of:
- R 1 and R 2 are H, CH 3 , C 2 H 5 , C 3 H 7 , C 4 H 9 , CF 3 , OCH 3 , F, CI, or Br;
- R 3 is H, CH 3 , C 2 H 5 , C 2 H 5 , C 4 H 9 , COOH, COOCH 3 , COOC 2 H 5 , COOC 2 H 5 , or
- this invention provides a method for stabilizing weight comprising chronic administration of an agent that stimulates CPT-1 activity in an amount that does not significantly inhibit FAS.
- the agent is administered in an amount sufficient to increase fatty acid oxidation.
- the agent is administered in an amount sufficient to antagonize malonyl CoA inhibition of CPT-1.
- the agent is administered in an amount sufficient to increase malonyl CoA level.
- malonyl CoA level upon administration of the agent, malonyl CoA level is not substantially increased.
- Substantial increase in malonyl CoA level as contemplated herein is equivalent to about one-half the Kj for malonyl CoA inhibition of CPT-1.
- this invention provides a method of screening for agents that induce weight loss, comprising determining whether a candidate weight loss agent stimulates CPT-1 activity; and selecting an agent that stimulates CPT-1 activity.
- this method further comprises determining whether the candidate weight loss agent is an antagonist of malonyl CoA inhibition of CPT-1, and candidate weight loss agents are selected that obviate malonyl CoA inhibition of CPT-1.
- this invention provides a therapeutic composition comprising an agent that stimulates CPT-1 activity and L-carnitine.
- the therapeutic composition comprises an antagonist of malonyl CoA inhibition of CPT-1.
- this invention provides a nutritional composition comprising nutritionally sufficient amounts of fats, carbohydrates and amino acids, said composition further comprising an antagonist of malonyl CoA inhibition o f C PT- 1 a nd L-carnitine.
- a nutritional composition comprising nutritionally sufficient amounts of fats, carbohydrates and amino acids, said composition further comprising an antagonist of malonyl CoA inhibition o f C PT- 1 a nd L-carnitine.
- o ne m ode t he n utritional c omposition i s adapted for parenteral administration.
- C75 concomitantly stimulated CPT-1 activity and fatty acid oxidation in vitro while inhibiting FAS.
- C75 abrogated the inhibitory effect of malonyl-CoA on CPT-1 activity in vitro.
- C75 increased cellular ATP levels.
- Figure 1 shows the effect of C75 on fatty acid oxidation in MCF-7 cells, compared to the effect of Etomoxir.
- Figure 2 shows concentration dependent stimulation of CPT-1 activity by C75 and inhibition by malonyl CoA.
- Figure 3 shows reversible stimulation of CPT-1 by C75.
- FIG. 4 shows stimulation of CPT-1 by various C75 analogs.
- Figure 5 shows concentration dependent enhancement of cellular ATP levels by C75 in MCF-7 cells.
- Figure 6 shows concentration dependent stimulation of fatty acid oxidation by C75 in mouse adipocytes.
- Figure 7 shows concentration dependent enhancement of cellular ATP levels by C75 in mouse adipocytes.
- Figure 8 shows respiratory exchange ratio (RER) measured by indirect calorimetry for mice in the absence (A) and presence (B, C) of C75.
- RER respiratory exchange ratio
- C-75 fatty acid synthase
- CPT-1 carnitine pahnitoyltransferase-1
- Cerulenin in contrast, leads to reduced CPT-1 activity and reduced fatty acid oxidation through generation of high malonyl-CoA levels from FAS inhibition.
- C75 treatment of MCF-7 cells in vitro stimulated CPT-1 activity from 150- 160%. There was also a concomitant increase in fatty acid oxidation.
- C75 a carbon chain length of C6-C16 was optimum for CPT-1 stimulatory activity.
- malonyl-CoA is no longer able to inhibit CPT-1 activity, suggesting that in addition to its stimulatory effect, C75 also prevents malonyl-CoA inhibition of CPT-1.
- the peripheral (non-CNS) weight loss effect of C-75 is at least in part due to CPT-1 stimulation and increased fatty acid oxidation with concomitant fatty acid synthesis inhibition.
- C75 and its family of ⁇ -methylene- ⁇ -butyrolactones directly interact with CPT-1 leading to increased CPT-1 enzymatic activity and fatty acid oxidation.
- the chemical structure of C75 and numerous analogs, a s well as methods of synthesizing these analogs, are disclosed in U.S. Patent No. 5,981,575, which is incorporated herein by reference.
- the stimulatory effect of C75 is related to the length of the saturated carbon side chain, with the optimum length between 6- 18 carbon atoms.
- C75 is the prototype agent for stimulation of CPT-1; reference to C75 hereinafter includes other suitable agents which stimulate CPT-1 activity, except where indicated otherwise by context.
- C-75 abolishes the inhibitory effect of malonyl-CoA on CPT-1 activity.
- C75 exhibits kinetic features of a slow-binding inhibitor with purified FAS (1), its interaction with CPT-1 appears rapid and competitive.
- the stimulatory effect of C75 upon fatty acid oxidation may be due to either its direct stimulation of CPT-1 activity, its interference of malonyl-CoA inhibition of CPT-1, or both.
- the effects of C75 are not restricted to murine CPT-1, as human CPT-1 was similarly affected.
- C75 also increased ATP levels in both the human and murine cells.
- C75 The effect of C75 on fatty acid metabolism in vivo mirrored the alterations seen on a cellular level.
- C75 and its family of ⁇ -methylene- ⁇ -butyrolactones appear to act as competitive agonists of CPT-1.
- This agonist activity of C75 appears to overcome inhibitory effects of malonyl CoA on the same enzyme.
- the increased fatty acid oxidation induced by C75 is an important mechanism accounting for marked reduction in adiposity seen during C75 treatment of mice.
- this invention describes a method to develop therapeutics that selectively enhance fatty acid oxidation, increase energy production, and reduce adiposity while preserving lean mass, through the pharmacological stimulation of CPT-1 activity.
- compositions containing C75 and/or other agents that stimulate CPT-1 are within the skill of the art, particularly in view of the description in U.S. Patent No. 5,981,575, the text of which is incorporated herein by reference.
- CPT-1 stimulating agents to increase energy production by administering the agents contemporaneously with fatty acids or compounds containing fatty acid residues is also within the skill of the art, particularly in view of the nutritional compositions disclosed in U.S. Patent No. 4,434,160, the text of which is incorporated herein by reference.
- Example 1 Paradoxical Effects of a Fatty Acid Synthase Inhibitor.
- Cerulenin an FAS inhibitor, increases malonyl-CoA amount in MCF-7 cells (3).
- cerulenin causes inhibition of fatty acid oxidation through the malonyl-CoA inhibition of CPT-1 (Thupari, et al. (2001) Biochem. Biophys. Res. Comm., 285:217-223).
- C75 treatment of MCF-7 cells resulted in a >5-fold increase in malonyl-CoA through C75 inhibition of fatty acid synthase (FAS) (3).
- FAS fatty acid synthase
- Human breast cancer cell line MCF-7 was obtained from the American Type Culture Collection. 1 x 10 6 MCF-7 cells were plated in T-25 flasks in triplicate and incubated overnight at 37°C. Drugs were then added as indicated diluted from 5 mg/ml stock in DMSO. After 2 hours, medium with drugs was removed and cells were preincubated for 30 min. with 1.5 ml of the following buffer: 114 mM NaCl, 4.7 mM KC1, 1.2 mM KH 2 PO 4 , 1.2 mM MgSO 4 , glucose 11 mM.
- C75 treatment increased rather than decreased fatty acid oxidation in MCF-7 cells. This implies a direct effect of C75 upon carnitine palmitoyltransferase-1 (CPT-1).
- Example 2 C75 Stimulates Activity of Human CPT-1.
- CPT-1 activity was assayed in MCF-7 cells by the following published procedure: MCF-7 cells were plated in DMEM with 10% fetal bovine serum at 10 6 cells in 24-well plates in triplicate. Following overnight incubation at 37°C, the medium was removed and replaced with 700 ⁇ l of assay medium consisting of: 50 mM imidazole, 70 mM KC1, 80 mM sucrose, 1 mM EGTA, 2 mM MgCl 2 , 1 mM DTT, 1 mM KCN, 1 mM ATP, 0.1% fatty acid free bovine serum albumin, 70 ⁇ M palmitoyl-CoA, 0.25 ⁇ Ci [methyl- 14 C] L-carnitine, 40 ⁇ g digitonin with or without 20 ⁇ M malonyl-CoA.
- MCF-7 cells were treated with C75 at 10 or 20 ⁇ g/mL for 1 hr before CPT-1 activity was assayed.
- the assay was performed with the C75 and malonyl-CoA concentrations indicated ("M" indicates malonyl-CoA at 20 uM).
- the level of malonyl- CoA inhibition of the CPT-1 activity is consistent with the activity of the liver isoform of CPT-1 in MCF-7 cells.
- the Kj of malonyl-CoA for the liver isoform of CPT-1 is ⁇ 7 ⁇ M while the Kj for the muscle isoform of CPT-1 is 0.07 ⁇ M.
- MCF-7 cells express predominantly the liver isoform of CPT-1 (consistent with the immunoblot analysis).
- MCF-7 cells were untreated (left bar) or treated with C75 at 20 ⁇ g/ml for one hour before CPT-1 activity was measured (middle and right bars).
- C75 was removed from the assay buffer and replaced with buffer (middle bar) or malonyl-CoA 20 ⁇ M was added (left & right bars).
- the optimum carbon chain length for CPT-1 activation is between 6 and 16 carbons.
- Example 4. Enhanced Fatty Acid Oxidation from CPT-1 Stimulation Produces ATP.
- ATP was elevated in MCF-7 cells following C75 treatment.
- 1 x 10 5 MCF-7 cells were plated in 96 well plates. Cells were treated with C75 or vehicle. After 2 hours, ATP was measured using a luciferase assay using the ATP Bioluminescence Kit CLS II (Roche) following the manufacturer's protocol. Plates were read by a Perkin Elmer Wallac Victor 2 1420 luminometer.
- C75 treatment at 10 ⁇ g/ml and 20 ⁇ g/ml both resulted in a significant increase in total cellular ATP (see Figure 5; p 0.0001; pO.OOOl compared to control, two-tailed t-test, Prism 3.0). Similar results were obtained after lhr incubation with C75. Thus, cellular energy production increased as a result of C75 increasing fatty acid oxidation.
- Example 5 C75 Stimulates Activity of Muscle Form CPT-1.
- differentiated (non-transformed) mouse NTH 3T3-L1 adipocytes were used in assays similar to those performed with the MCF-7 cells.
- 3T3-L1 cells were obtained from the American Type Culture Collection, and cells were cultured in DMEM with high glucose (4.5 g/1) (Gibco 12100-046) with 10%o fetal calf serum and Biotin (Sigma B-4639) 0.008 g/L. Differentiation was initiated three days after the cells were confluent, when the standard culture medium was r eplaced w ith d ifferentiation m edium.
- T he differentiation m edium contained standard culture medium to which the following were added to achieve the final concentrations: methylisobutylxanthine (MIX) 0.5 mM, dexamethasone (DEX) 1 ⁇ M, and insulin 10 ⁇ g/ml. After 48 hrs, the differentiation medium was replaced with post-differentiation medium which contained insulin at the above concentration, without MIX and DEX. The differentiated cells were ready to be used for experiments in 7-10 days.
- MIX methylisobutylxanthine
- DEX dexamethasone
- C75 increased CPT-1 activity and fatty acid metabolism in the NTH 3T3-L1 cells differentiated into adipocytes.
- One week post differentiation cells were treated with either vehicle control or C75 for 2 hours at doses indicated below.
- CPT-1 activity, fatty acid oxidation, and total cellular ATP were measured as described in Examples 2, 1, and 4.
- C75 treatment of 3T3-L1 adipocytes led to a 377% increase in CPT-1 activity above control (p ⁇ 0.0001, two-tailed t-test, Prism 3.0).
- the enhanced fatty acid oxidation induced by C75 is likely responsible for the marked reduction in adipose tissue mass seen with C75 administration in vivo.
- Example 6 In vivo Stimulation of CPT-1 Shifts Metabolism to Fatty Acid Oxidation.
- C75 In keeping with the C75 effect on both human and urine CPT-1 and fatty acid metabolism, C75 induces a profound and rapid stimulation of fatty acid oxidation in vivo.
- Mice were maintained in the Oxymax calorimeter (Oxymax Equal Flow System®, Columbus Instruments, Columbus, OH). Oxygen consumption and CO production was measured in up to four mice simultaneously using the indirect calorimeter. Measurements were recorded every 15 minutes over the entire course of the experiments.
- the respiratory exchange ratio (RER) was calculated by the Oxymax® software version 5.9. RER is defined as the ratio of CO 2 to O 2 at any given time irrespective if equilibrium was reached. Mice were maintained on water and mouse chow ad libitum.
- C75 treatment led to a rapid, profound increase in fatty acid oxidation as measured by RER.
- C75 treated animals are able to significantly reduce adipose mass and reverse fatty liver, by allowing fatty acid oxidation to occur despite the high levels of malonyl-CoA generated during FAS inhibition in vivo.
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Abstract
Description
Claims
Priority Applications (14)
Application Number | Priority Date | Filing Date | Title |
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BR0307421-8A BR0307421A (en) | 2002-02-08 | 2003-02-10 | Stimulation of cpt-1 as a brake to reduce weight |
EP03710928A EP1471906A4 (en) | 2002-02-08 | 2003-02-10 | Stimulation of cpt-1 as a means to reduce weight |
US10/503,605 US20050143467A1 (en) | 2002-02-08 | 2003-02-10 | Stimulation of cpt-1 as a means to reduce weight |
CA002474884A CA2474884A1 (en) | 2002-02-08 | 2003-02-10 | Stimulation of cpt-1 as a means to reduce weight |
KR10-2004-7012208A KR20040082417A (en) | 2002-02-08 | 2003-02-10 | Stimulation of cpt-1 as a means to reduce weight |
EA200401052A EA007029B1 (en) | 2002-02-08 | 2003-02-10 | Stimulation of cpt-1 as a means to reduce weight |
AU2003215111A AU2003215111A1 (en) | 2002-02-08 | 2003-02-10 | Stimulation of cpt-1 as a means to reduce weight |
JP2003565467A JP2005523270A (en) | 2002-02-08 | 2003-02-10 | Promotion of CPT-1 as a way to lose weight |
MXPA04007556A MXPA04007556A (en) | 2002-02-08 | 2003-02-10 | Stimulation of cpt-1 as a means to reduce weight. |
IL163312A IL163312A (en) | 2002-02-08 | 2004-08-02 | Use of an agent that stimulates cpt-1 activity for the manufacture of a medicament for treating obesity |
US10/917,525 US20050106217A1 (en) | 2002-02-08 | 2004-08-13 | Stimulation of CPT-1 as a means to reduce weight |
US11/537,968 US7459481B2 (en) | 2002-02-08 | 2006-10-02 | Stimulation of CPT-1 as a means to reduce weight |
US12/266,425 US20090124684A1 (en) | 2002-02-08 | 2008-11-06 | Stimulation Of CPT-1 As A Means To Reduce Weight |
AU2008249144A AU2008249144A1 (en) | 2002-02-08 | 2008-11-20 | Stimulation of CPT-1 as a means to reduce weight |
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PCT/US2003/003839 WO2003066043A1 (en) | 2002-02-08 | 2003-02-10 | Stimulation of cpt-1 as a means to reduce weight |
Country Status (12)
Country | Link |
---|---|
US (4) | US20050143467A1 (en) |
EP (1) | EP1471906A4 (en) |
JP (2) | JP2005523270A (en) |
KR (1) | KR20040082417A (en) |
CN (1) | CN1313089C (en) |
AU (2) | AU2003215111A1 (en) |
BR (1) | BR0307421A (en) |
CA (1) | CA2474884A1 (en) |
EA (1) | EA007029B1 (en) |
IL (1) | IL163312A (en) |
MX (1) | MXPA04007556A (en) |
WO (1) | WO2003066043A1 (en) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1758577A4 (en) * | 2004-05-26 | 2010-05-05 | Fasgen Llc | Novel compounds, pharmaceutical compositions containing same, and methods of use for same |
ES2405259A1 (en) * | 2011-11-25 | 2013-05-30 | Centro De Investigación Biomédica En Red Fisiopatología De La Obesidad Y Nutrición (Ciberobn) | Use of the enanti¿mero () -c75 for the treatment of obesity. (Machine-translation by Google Translate, not legally binding) |
Families Citing this family (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EA007029B1 (en) * | 2002-02-08 | 2006-06-30 | Джон Хопкинс Юниверсити Скул Оф Медсин | Stimulation of cpt-1 as a means to reduce weight |
KR101087559B1 (en) * | 2002-07-09 | 2011-11-29 | 더 존스 홉킨스 유니버시티 | Novel compounds and pharmaceutical compositions containing same |
EP1732572A4 (en) * | 2004-03-18 | 2007-04-18 | Fasgen Llc | Control of feeding behavior by changing neuronal energy balance |
ATE466838T1 (en) * | 2005-06-06 | 2010-05-15 | Hoffmann La Roche | SULFONAMIDE DERIVATIVES AS LIVER CARNITININE PALMITOYL TRANSFERASE INHIBITORS |
US20100168218A1 (en) * | 2005-07-26 | 2010-07-01 | Kuhajda Francis P | Method of reducing food intake |
ATE418603T1 (en) * | 2005-08-29 | 2009-01-15 | Hoffmann La Roche | CRYSTAL STRUCTURES OF CARNITINE PALMITOYLTRANSFERASE-2 (CPT-2) AND THEIR USE |
WO2013155528A2 (en) * | 2012-04-13 | 2013-10-17 | Fasgen, Inc. | Methods for reducing brain inflammation, increasing insulin sensitivity, and reducing ceramide levels |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US574639A (en) | 1897-01-05 | Gold-saving device | ||
US4434160A (en) * | 1980-07-11 | 1984-02-28 | Leopold & Co. Chem. Pharm. Fabrik Gesellschaft M.B.H. | Nutrient solution for complete parenteral feeding and for increased energy production |
US5981575A (en) | 1996-11-15 | 1999-11-09 | Johns Hopkins University, The | Inhibition of fatty acid synthase as a means to reduce adipocyte mass |
WO2004005277A1 (en) | 2002-07-09 | 2004-01-15 | Fasgen, Inc. | Novel compunds, pharmaceutical compositions containing same, and methods of use for same |
WO2004006835A2 (en) | 2002-07-01 | 2004-01-22 | Fasgen, Llc. | Novel compounds, pharmaceutical compositions containing same, and methods of use for same |
Family Cites Families (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5914326A (en) * | 1997-08-08 | 1999-06-22 | Ambi Inc. | Method for promoting weight and fat loss |
AU5802499A (en) * | 1998-09-01 | 2000-03-21 | Amway Corporation | Diet composition and method of weight management |
AU784495B2 (en) * | 1999-11-12 | 2006-04-13 | Johns Hopkins University School Of Medicine, The | Treating cancer by increasing intracellular malonyl coa levels |
AU2001238515A1 (en) * | 2000-02-16 | 2001-08-27 | The John Hopkins University School Of Medicine | Weight loss induced by reduction in neuropeptide y level |
WO2002079501A1 (en) * | 2001-03-30 | 2002-10-10 | Trustees Of Boston University | Methods and reagents for identifying weight loss promoters and therapeutic uses therefor |
EA007029B1 (en) * | 2002-02-08 | 2006-06-30 | Джон Хопкинс Юниверсити Скул Оф Медсин | Stimulation of cpt-1 as a means to reduce weight |
US20040161803A1 (en) * | 2002-04-01 | 2004-08-19 | Corkey Barbara E. | Methods and reagents for identifying weight loss promoters and therpeutic uses therefor |
-
2003
- 2003-02-10 EA EA200401052A patent/EA007029B1/en unknown
- 2003-02-10 US US10/503,605 patent/US20050143467A1/en not_active Abandoned
- 2003-02-10 CN CNB038050145A patent/CN1313089C/en not_active Expired - Fee Related
- 2003-02-10 WO PCT/US2003/003839 patent/WO2003066043A1/en active Application Filing
- 2003-02-10 AU AU2003215111A patent/AU2003215111A1/en not_active Abandoned
- 2003-02-10 KR KR10-2004-7012208A patent/KR20040082417A/en not_active Application Discontinuation
- 2003-02-10 CA CA002474884A patent/CA2474884A1/en not_active Abandoned
- 2003-02-10 EP EP03710928A patent/EP1471906A4/en not_active Withdrawn
- 2003-02-10 BR BR0307421-8A patent/BR0307421A/en not_active IP Right Cessation
- 2003-02-10 MX MXPA04007556A patent/MXPA04007556A/en active IP Right Grant
- 2003-02-10 JP JP2003565467A patent/JP2005523270A/en active Pending
-
2004
- 2004-08-02 IL IL163312A patent/IL163312A/en not_active IP Right Cessation
- 2004-08-13 US US10/917,525 patent/US20050106217A1/en not_active Abandoned
-
2006
- 2006-10-02 US US11/537,968 patent/US7459481B2/en not_active Expired - Fee Related
-
2008
- 2008-11-06 US US12/266,425 patent/US20090124684A1/en not_active Abandoned
- 2008-11-20 AU AU2008249144A patent/AU2008249144A1/en not_active Abandoned
-
2009
- 2009-10-20 JP JP2009241309A patent/JP2010047594A/en active Pending
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US574639A (en) | 1897-01-05 | Gold-saving device | ||
US4434160A (en) * | 1980-07-11 | 1984-02-28 | Leopold & Co. Chem. Pharm. Fabrik Gesellschaft M.B.H. | Nutrient solution for complete parenteral feeding and for increased energy production |
US5981575A (en) | 1996-11-15 | 1999-11-09 | Johns Hopkins University, The | Inhibition of fatty acid synthase as a means to reduce adipocyte mass |
WO2004006835A2 (en) | 2002-07-01 | 2004-01-22 | Fasgen, Llc. | Novel compounds, pharmaceutical compositions containing same, and methods of use for same |
WO2004005277A1 (en) | 2002-07-09 | 2004-01-15 | Fasgen, Inc. | Novel compunds, pharmaceutical compositions containing same, and methods of use for same |
Non-Patent Citations (1)
Title |
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See also references of EP1471906A4 |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1758577A4 (en) * | 2004-05-26 | 2010-05-05 | Fasgen Llc | Novel compounds, pharmaceutical compositions containing same, and methods of use for same |
ES2405259A1 (en) * | 2011-11-25 | 2013-05-30 | Centro De Investigación Biomédica En Red Fisiopatología De La Obesidad Y Nutrición (Ciberobn) | Use of the enanti¿mero () -c75 for the treatment of obesity. (Machine-translation by Google Translate, not legally binding) |
Also Published As
Publication number | Publication date |
---|---|
AU2008249144A1 (en) | 2008-12-11 |
CN1638758A (en) | 2005-07-13 |
MXPA04007556A (en) | 2005-12-05 |
US20050106217A1 (en) | 2005-05-19 |
US20070087037A1 (en) | 2007-04-19 |
EP1471906A4 (en) | 2006-02-01 |
EA007029B1 (en) | 2006-06-30 |
CN1313089C (en) | 2007-05-02 |
US20090124684A1 (en) | 2009-05-14 |
AU2003215111A1 (en) | 2003-09-02 |
JP2005523270A (en) | 2005-08-04 |
EP1471906A1 (en) | 2004-11-03 |
BR0307421A (en) | 2004-12-28 |
KR20040082417A (en) | 2004-09-24 |
US20050143467A1 (en) | 2005-06-30 |
JP2010047594A (en) | 2010-03-04 |
IL163312A (en) | 2011-12-29 |
US7459481B2 (en) | 2008-12-02 |
CA2474884A1 (en) | 2003-08-14 |
EA200401052A1 (en) | 2005-02-24 |
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