WO2015028456A1

WO2015028456A1 - PPAR modulators

Info

Publication number: WO2015028456A1
Application number: PCT/EP2014/068052
Authority: WO
Inventors: Denis Marcel Barron; Sofia MOCO; Yann RATINAUD
Original assignee: Nestec S.A.
Priority date: 2013-08-28
Filing date: 2014-08-26
Publication date: 2015-03-05

Abstract

The present invention relates to the field of metabolic and inflammatory disorders and aims to identify natural compounds that can be used effectively in this field. In particular, the (I) for use in the treatment or prevention of a metabolic or chronic inflammatory disorder.

Description

Patent case 13331 : PPAR modulators

The present invention relates to the field of metabolic disorders and inflammation and identifies natural compounds that can be used effectively in this field.

Diabetes mellitus is a metabolic condition characterized primarily by high blood glucose levels that result from the body's inability to make or use insulin. Hyperglycemia can lead to numerous clinical complications including blindness, limb amputations, heart attack or stroke.

In 2004, the World Health Organization (WHO) estimated that 3.4 million people died from consequences of high fasting blood sugar. Moreover, in 201 1 it was estimated that 347 million people worldwide have diabetes (Danaei, Lancet, 201 1 , 378(9785):31-40) and it is projected that diabetes will be the 7th leading cause of death in 2030 (Global status report on noncommunicable diseases 2010. Geneva, World Health Organization, 201 1 ).

More than 80% of diabetes deaths occur in low- and middle-income countries (Mathers and Loncar, World Health Organization, 2005).

Healthy diet, regular physical activity, maintaining a normal body weight and avoiding tobacco use can prevent or delay the onset of type 2 diabetes (T2D).

The most common types of diabetes are insulin-dependent diabetes (Type-1 diabetes, T1 D) and T2D, which is by far the most abundant type. The increase in T2D is mainly driven by increasing obesity rates. Today, more than 1 .1 billion people are estimated to be overweight, of which around 320 million are obese.

The pathophysiology of the development of T2D is complex and multifactorial.

Obesity, sedentary life style and/or increased age may lead to insulin resistance and to increased circulating insulin concentrations over time.

At some point a loss of control of blood glucose begins to emerge, resulting in impaired glucose tolerance (IGT) or impaired fasting glucose (IFG). Ultimately T2D may result. Therefore insulin resistance, IGT and IFG refer to metabolic states intermediate between normal glucose homeostasis and diabetes.

l As glucose is an essential nutrient for the human body, its circulating levels must be carefully maintained constant, in order to supply adequate amounts to peripheral tissues. An impairment of glucose homeostasis is a typical feature of T2D. Patients with T2D exhibit increased hepatic glucose production (HGP), which is identified as the main cause of fasting hyperglycaemia and is associated with a reduced plasma glucose clearance (Gastaldelli A, et al., Diabetes 2000; 49:1367-1373), and a 25-45% reduced synthesis of glycogen compared with non-diabetic subjects (Roden M, et al., Best Pract Res Clin Endocrinol Metab. 2003;17:365-83 ).

Limiting blood glucose peaks after a meal is consequently important for the prevention, alleviation or treatment of metabolic disorders, such as insulin resistance, IGT and IFG and diabetes, e.g., T2D.

Limiting glucose peaks in diabetic subjects also constitutes an important target of the overall glycemic control strategy.

Healthy eating habits and a physically active lifestyle are the best measures to prevent metabolic disorders. Caloric restriction, sugar intake control or medication are further preventive measures or treatments that are currently used in this respect.

Inflammation is the complex biological response of tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. It is generally a protective attempt by the organism to remove the injurious stimuli as well as initiate the healing process for the tissue. However, non-appropriately regulated inflammation can lead to several diseases irrespective of the age of the subject.

Ageing is often associated with a dysregulation of the immune system, such as a noted decline in cell-mediated immune response concomitant with an increased humoral immune dysfunction (e.g. lower response to vaccine). Ageing is furthermore often associated with a status of low-grade inflammation. In particular many elderly subjects are at increased risk of infectious and non-infectious diseases that contribute to morbidity and mortality.

Unwanted inflammation can be treated by proper medication. However, medication may result in unwanted side effects and often requires the supervision of medical personnel. There remains to be a need in the art for further alternative and natural compounds that can be used or assist in the prevention, alleviation or treatment of metabolic disorders and inflammation.

The present inventors have addressed this need. Consequently, it was the object of the present invention to provide the art with natural compounds that can be used in the prevention, alleviation or treatment of metabolic disorders and inflammation.

The practice of the present invention will employ, unless otherwise indicated, conventional techniques of chemistry, molecular biology, microbiology, recombinant DNA and immunology, which are within the capabilities of a person of ordinary skill in the art. Such techniques are explained in the literature. See, for example, J. Sambrook, E. F. Fritsch, and T. Maniatis, 1989, Molecular Cloning: A Laboratory Manual, Second Edition, Books 1 -3, Cold Spring Harbor Laboratory Press; Ausubel, F. M. et al. (1995 and periodic supplements; Current Protocols in Molecular Biology, ch. 9, 13, and 16, John Wiley & Sons, New York, N.Y.); B. Roe, J. Crabtree, and A. Kahn, 1996, DNA Isolation and Sequencing: Essential Techniques, John Wiley & Sons; J. M. Polak and James O'D. McGee, 1990, In Situ Hybridization: Principles and Practice; Oxford University Press; M. J. Gait (Editor), 1984, Oligonucleotide Synthesis: A Practical Approach, Irl Press; D. M. J. Lilley and J. E. Dahlberg, 1992, Methods of Enzymology: DNA Structure Part A: Synthesis and Physical Analysis of DNA Methods in Enzymology, Academic Press; and E. M. Shevach and W. Strober, 1992 and periodic supplements, Current Protocols in Immunology, John Wiley & Sons, New York, NY. Each of these general texts is herein incorporated by reference.

The present inventors have found that certain natural products can effectively modulate human peroxisome proliferator-activated receptors (hPPARs), which makes them interesting candidates for, e.g., nutritional applications.

The peroxisome proliferator-activated receptors (PPARa, γ and β/δ) are nuclear receptors that act as a transcription factor upon activation. These nuclear factors are expressed with distinct patterns in many cell types. They regulate the transcription and expression of key target genes with a wide range of effects on immune response and metabolism. There are a variety of potential endogenous or synthetic ligands that activates PPARs with varying affinities and specificities, resulting in transcriptional activation or repression of target genes. PPARy activators are involved in carbohydrate and lipid metabolism, leading to the improvement of insulin sensitivity in muscle, liver and adipose tissue.

Activators of PPARy have emerged as potent insulin sensitizers used in the treatment of T2D. Increased levels of circulating free fatty acids and lipid accumulation in non-adipose tissue have been implicated in the development of insulin resistance. This situation is improved by PPARy activators, which promote fatty acid storage in fat depots and regulate the expression of adipocyte-secreted hormones that impact on glucose homeostasis

(Rangwala and Lazar, Trends Pharmacol Sci. 2004 Jun;25(6):331 -6).

PPARy is also expressed in major immune cell types and enterocytes and a lot of evidence suggests that this nuclear receptor is also an important regulator of the inflammatory response. Indeed, in several rodent models of inflammatory or autoimmune diseases, ligands for PPARy (and to some extent other PPARs) provide health benefits. Similar to rodents, PPARy activation might have therapeutic activity in human diseases as a PPARy synthetic ligand was recently reported to have therapeutic activity in human patients with ulcerative colitis as a first demonstration (Lewis J.D., et al., Am. J. Gastroenterol. 2001 , 96(12): 3323- 3328). Endogenous or synthetic PPARy ligands have been shown to downregulate diverse components of the inflammatory response in epithelial, innate and adaptive immune cells such as proinflammatory cytokines, chemokines and costimulatory molecules. Ligand-bound PPARy repress the expression of inflammatory response genes via a so-called ligand dependent transrepression mechanism. PPARy decreases the inflammatory response of many cardiovascular cells, particularly endothelial cells (Hamblin et al., Antioxid Redox Signal. 2009 June; 1 1 (6): 1415-1452). Recently pioglitazone, a PPAR-γ agonist, has been shown to be effective in reducing inflammation in Parkinson's Disease models (Swanson et al., Journal of Neuroinflammation 201 1 , 8:91 ). The present invention relates in part to compounds, and compositions comprising said compounds, for use in the treatment or prevention of disorders which are treatable or preventable by activation of a PPAR, in particular PPARy and/or PPARa.

There is provided herein compounds and compositions comprising said compounds, wherein the compounds are selected from Group 1 : Group 1

for use in the treatment or prevention of a metabolic or inflammatory disorder. The metabolic or inflammatory disorder according to the present invention is treatable or preventable by activation of a PPAR, preferably PPARy and/or PPARa.

Preferably, the compound for use in the present invention is selected from Group 2:

Group 2

(-)-Podophyllotoxin Picropodophyllotoxin (-)-Epipodophyllotoxin Isopicropodophyllin

Epiisopodophyllotoxin Epiisopicropodophyllin Epipicropodophyllotoxin Isopodophyllotoxin

(-)-Deoxypodophyllotoxin (-)-Morelensin Angeloylpodophyllotoxin

4'-D

The compounds may be present in racemic or enantiomeric form. Preferably the

stereoisomers depicted have an optical purity of >= 90 %, 98%, 99%, 99.5 or 99.9

enantiomeric excess (e.e.).

There is also provided herein a method of treating or preventing a metabolic or inflammatory disorder in a subject comprising administering a compound selected from Group 1 or Group 2 or a composition comprising said compound to said subject.

The compounds of the present invention may be oxidized to active products in-vivo (Lee et al. Rapid Commun. Mass Spectrum. 2008, 22, 52-58). Such oxidized products are also encompassed by the present invention.

By way of example, the following compounds may be oxidized to:

Preferably the PPAR referred to herein is human PPAR (hPPAR).

There is also provided herein the use of a compound selected from Group 1 or Group 2 as a modulator of PPARy and/or PPARa activities.

There is also provided herein a method of activating PPARy and/or PPARa in a subject comprising administering a compound selected from Group 1 or Group 2, or a composition comprising said compound, to said subject.

The invention also relates to the use of at least one compound selected from Group 1 or Group 2 for the preparation of a composition to treat or prevent a metabolic or inflammatory disorder.

The compounds and compositions described herein may also be used for the treatment or prevention of cardiovascular disorders.

The compounds of the invention belong to lignans and may be found in various organs of some plants.

The inventors currently believe that the compounds general effectiveness against metabolic and inflammatory disorders is due to the mechanism of action via hPPARs, in particular PPARy and/or PPARa.

Consequently, it is particularly preferred if the metabolic disorder is selected from the group consisting of insulin resistance, impaired glucose tolerance, impaired fasting glucose and diabetes, in particular T2D. All these disorders are directly linked to PPARy ligands as PPARy activation leads to the improvement of insulin sensitivity in muscle, liver and adipose tissue.

Preferably the metabolic disorder is diabetes, in particular T2D. In one embodiment, the metabolic disorder is not syndrome X.

The disorders referred to herein may have a genetic origin.

Typical inflammatory disorders that can be treated or prevented in accordance with the present invention include chronic inflammations such as inflammatory bowel disease, Crohn's disease, ulcerative colitis, necrotizing enterocolitis, inflammatory bowel syndrome, liver inflammation, systemic lupus, obesity-associated inflammation, or age-related low-grade inflammation.

The compounds and compositions of the present invention may also be used to alleviate inflammation. While inflammation often may be a secondary disorder or symptom resulting from another disease, it often represents a significant reason for discomfort, pain and unwellness. Alleviating such inflammation related symptoms may represent a significant relief for a person or animal suffering from inflammation based symptoms.

The compounds and compositions of the present invention may be administered to humans or animals, for example pet animals, such as dogs, cats, birds, rabbits, or guinea pigs. The compounds and compositions of the present invention may, for example, be administered orally, enterally, or parenterally. They may be provided in any galenical form normally available for the selected mode of administration. In a particularly preferred embodiment, the compounds and compositions are administered orally.

The compounds and compositions of the present invention may be administered to any age group. For example, the composition of the present invention may be administered to infants, teenagers, adults or the elderly.

For example, compounds and compositions of the present invention may be administered together with foods with high sugar content, such as sweet dishes, deserts or confectionary.

The composition of the present invention may, for example, be selected from the group consisting of food compositions, food products, drinks, pet food products, dairy products, nutritional formulas, powdered nutritional formulations to be reconstituted in milk or water, food additives, nutritional supplements, nutraceuticals, pharmaceutical compositions, and/or food ingredients. In one embodiment, the composition is a medical food. The composition may be provided in the form of a shelf stable powder.

In one embodiment, the composition of the present invention is a drinkable composition.

In the case of oral use in accordance with the invention for oral administration, the use of an ingestible support or carrier is preferred. The ingestible support or carrier may be of diverse nature depending on the type of composition under consideration.

Milk, yogurt, cheese, fermented milks, milk-based fermented products, ice creams, cereal- based products or fermented cereal-based products, milk-based powders, infant and baby formulas, food products of confectionary, chocolate or cereal type, animal feed, in particular for domestic animals, tablets, gel capsules or lozenges, oral supplements in dry form, oral supplements in liquid form, and food for medical purpose are especially suitable for use as ingestible support or carrier.

The composition according to the invention which is to be administered orally may be formulated for example in the form of coated tablets, gel capsules, gels, emulsions, tablets, capsules, hydrogels, food bars, compact or loose powders, liquid suspensions or solutions, confectionery products, fermented milks, fermented cheeses, chewing gum, toothpaste or spray solutions or food carriers.

Tablets or lozenges, oral supplements in dry form, oral supplements in liquid form, and food for medical purpose are suitable for use as dietetic or pharmaceutical supports or food carriers. The composition may be, for example, a food supplement, or a food for medical purpose, which may be formulated via the usual processes for in particular producing sugar-coated tablets, gel capsules, gels, emulsions, tablets, capsules and hydrogels allowing controlled release.

The formulating agents and excipients for oral compositions, and in particular for food supplements, are known in this field and will not be the subject of a detailed description herein.

The compound of Group 1 or Group 2 may be provided as a chemically pure compound. It may be synthesized chemically. It may also be provided as a plant extract. Typical known plant sources that may be used as source for the plant extract are, for example, selected from the genus: Abies (a-conidendrin), Anthriscus (deoxypodophyllotoxin, morelensin, angeloylpodophyllotoxin), Juniperus (deoxypodophyllotoxin), Linum (morelensin, polygamain), Picea (a-conidendrin), Podophyllum (deoxypodophyllotoxin, 4'- demethyldeoxypodophyllotoxin), Polygala (deoxypodophyllotoxin, 4'- demethyldeoxypodophyllotoxin, polygamain, polygamatin), Taxus (a-conidendrin).

Any extract may be used. For example, the extract may be a water extract, an alcoholic extract, and/or an extract with an organic solvent.

In one embodiment the extract is an alcoholic extract. In a further embodiment the extract is a water extract.

The compounds of the present invention can be isolated form plant extracts using conventional techniques. By way of example, the isolation of deoxypodophyllotoxin, morelensin and Angeloylpodophyllotoxin from Anthriscus sylvestris is described in Lim et al., Archives of Pharmacal Research , 1999, 22, Issue 2, pp 208-212) By way of further example, conventional purification methods of deoxypodophyllotoxin from the rhizomes of A. sylvestris utilize solid stationary phases such as silica gels (Van Uden et al., 1997, J Nat. Prod. 60, 401 -403; Jeong et al., 2007, Biol. Pharm. Bull. 30, 1340-1343; Yong et al., 2009, Bioorg. Med. Chem. Lett. 19, 4367-4371 ). Moreover, Quan et al. {J. Korean Soc. Appl. Biol. Chem. 2010, 53, 1 10-1 13) discloses a simple and rapid purification method of deoxypodophyllotoxin from the crude methanol extract of rhizomes of Anthriscus sylvestris using high-speed counter-current chromatography. The crude deoxypodophyllotoxin extract was separated using a two-phase solvent system composed of n-hexane/ethyl acetate/methanol/water (7:3:5:5, v/v). The chemical synthesis of the compounds used in the present invention can be performed using conventional methods well known in the art. By way of example, Wu et al. {Org. Lett. 2007, 9, 1 199-1202; Org. Lett. 2009, 11 , 597-560) reported the synthesis of podophyllotoxin and its analogues. Engelhardt et al. {Angew. Chem. Int. Ed. 2003, 42, 2487 - 2489) published a synthesis for (-)-epipodophyllotoxin, while Pelter et al. (Tetrahedron Asymmetry 1994, 5, 909-920) optimized an asymmetric synthesis of isopodophyllotoxin. Couture et al. {Bioorg. Med. Chem. 2000, 8, 21 13-2125) reported the synthesis of β-peltatin. Jones & Thompson {J. Chem. Soc. Perkin Trans. 1 1993, 2541 -2548) published a synthesis of (±)-4- deoxypodophyllotoxin. Bogucki & Charlton {J. Org. Chem. 1995, 60, 588-593) described the asymmetric synthesis of (-)-deoxypodophyllotoxin. Recently the synthesis of 4- deoxypodophyllotoxin by reduction of podophyllotoxin has been published by Wang et al. (J. Agric. Food Chem. 2013, 61 , 6336-6343). WO 2007/009201 describes the synthesis of lignin derivatives, including morelensin and polygamain. Tanoguchi et al. (Chem. Pharm. Bull. 1989, 37, 68-72) describes the synthesis of Hernandin and Fischer et al. (Org. Lett. 2004, 6, 1345-1348) describes the synthesis of a-Conidendrin. Angeloylpodophyllotoxin can be synthesized by esterification of commercially available podophyllotoxin with angelic anhydride. An example of AngeloyI podophyllotoxin synthesis is as follows: To a solution of 0.15 g of podophyllotoxin in 5 mL of anhydrous THF, is added 0.325 mL of a solution of 1 M NaHMDS in anhydrous THF, at 10°C. The reaction medium is stirred at 10°C for 10 min, after which a solution of 0.08 g of angelic anhydride in 2 mL of anhydrous THF is added. After stirring for 1 h at 10°C, the reaction medium is quenched by adding a saturated aqueous solution of NH₄CI. The medium is extracted with dichloromethane. The organic phase is dried on Na₂S0₄, filtered, and evaporated under reduced pressure. After purification of the residue by reversed phase chromatography, 47 mg of angeloypodophyllotoxin is isolated as a white powder. The compounds disclosed herein may also be commercially available, e.g. (-)- podophyllotoxin and picropodophyllotoxin (Sigma-Aldrich), isopicropodophyllin (Waterstone), β-peltatin (Quality Phytochemicals), (-)-deoxypodophyllotoxin (Quality Phytochemicals), 4'- demethyldeoxypodophyllotoxin (Quality Phytochemicals) and a-Conidendrin (Sigma-Aldrich) Further synthetic methods of lignans are disclosed in Masunari et al., Synthetic Communications 2001 , 31 (14), 2127-2136); and Yamaguchi et al., Chem. Pharm. Bull. (Tokyo) 1984, 32, 1754-60; Pelter et aljetrahedron Letters, 1985, 26(51 ), 6377-80 ; Takano et al., Heterocycles, 1987, 25(1 ), 69-73; Pelter et al., J. Chem. Soc. Perkin Transactions 1, 1988, 1972-1999, (6), 1615-23; Ogiku et al, Bull. Chem. Soc. Japan, 1992, 65(12), 3495-7; Pelter et al., J. Chem Soc. Perkin Transactions 1, 1993, (21 ), 2621 -9.

The present invention also encompasses derivatives of the compounds of Group 1 and Group 2 for the uses defined herein. Assays for determining the hPPAR modulating activity of the compounds described herein are well known in the art (see, for example, Forman et al., Cell 1995 83, 803-12; Han et al., Biol. Pharm. Bull. 2006, 1 ,1 10-3; Han et al., Diabetes 2008, 57,737-45. Epub 2007 Dec 7). One such method involves utilizing a reporter gene construct wherein PPAR binding is assayed by measuring luciferase activity (see e.g., Forman et al., Cell 1995, 83,803-12; Han et al., Biol. Pharm. Bull. 2006, 1 ,1 10-3; Han et al., Diabetes. 2008, 57,737-45. Epub 2007 Dec 7; US 2007244094). In more detail, when PPARs fix their ligands they are able to shuttle from cytoplasm to the nucleus of cells. Then, PPARs heterodimerize with co-receptors called Retinoid-X-Receptors (RXR). Heterodimeric transcription factors PPAR/RXR are responsible for PPARs-mediated transcriptional program. In this system, hPPARs are fused to Gal4. Gal4 is a yeast transcription activator which specifically binds a Gal4 responsive element so-called Upstream Activation Sequence (UAS)- this short section in a promoter region strongly activates gene transcription. Therefore, cotransfection of Gal4-hPPARs with UAS-luciferase constructs allows identification hPPARs activators. Activators will stimulate luciferase transcription resulting in the formation of a functional enzyme that converts substrate to detectable signal by a chemiluminescent reaction. Derivatives of the compounds in Group 1 and 2 preferably have PPARy and PPARa agonist activity that is substantially similar to (e.g. at least 70% activity), or greater than, that of the corresponding compound in Group 1 and 2.

In therapeutic applications, compounds or compositions are administered in an amount sufficient to at least partially cure or arrest the symptoms of the disease and its complications. An amount adequate to accomplish this is defined as "a therapeutically effective dose". Amounts effective for this purpose will depend on a number of factors known to those of skill in the art such as the severity of the disease and the weight and general state of the patient.

In prophylactic applications, compounds and compositions according to the invention are administered to a patient susceptible to or otherwise at risk of a particular disease in an amount that is sufficient to at least partially reduce the risk of developing a disease. Such an amount is defined to be "a prophylactically effective dose". Again, the precise amounts depend on a number of patient specific factors such as the patient's state of health and weight. The compounds and compositions of the present invention may be administered in a therapeutically effective dose or a prophylactically effective dose. The compounds or compositions may be administered immediately before or during a meal. For example, they may be an integral part of the meal.

To ensure a certain effectiveness of the composition of the present invention, the composition may contain a therapeutically effective dose or a prophylactically effective dose of the present invention per serving.

Those skilled in the art will understand that they can freely combine all features of the present invention described herein, without departing from the scope of the invention as disclosed. In particular, features described for the compound and composition of the present invention may be applied to the use of the present invention and vice versa. Further advantages and features of the present invention are apparent from the following Examples, Figures and Table.

Figure 1 shows the principle of hPPAR bioassay used for screening. The assays detect binding of a ligand to the hPPAR of interest by directly measuring luciferase activity. The ligand can be exogenic or endogeneously produced in the cell. When PPARs fixe their ligands they are able to shuttle from cytoplasm to the nucleus of HeLa cells. Then, PPARs heterodimerize with co-receptors called Retinoid-X-Receptors (RXR). Heterodimeric transcription factors PPAR/RXR are responsible for PPARs-mediated transcriptional program. In this system, hPPARs are fused to Gal4. Gal4 is a yeast transcription activator which specifically binds a Gal4 responsive element so-called Upstream Activation Sequence (UAS), this short section in a promoter region strongly activates gene transcription. Therefore, cotransfection of Gal4-hPPARs with UAS-luciferase constructs allows identification of modulators of hPPARs activity. Agonists will stimulate luciferase transcription resulting in the formation of a functional enzyme that converts substrate to detectable signal by a chemiluminescent reaction. Table 1 shows dose-responses effects of a selection of compounds at different concentrations (nM) for PPARa and PPARy activation. The AC50 and the maximum % activation are given.

Table 1 : Dose response effects of a selection of compounds for hPPARa and hPPARy activation. Results summary Average N=2 hPPAR-alpha hPPAR-gamma

EC50 Efficacy EC50 Efficacy

(nM) (%) (nM) (%)

hPPAR-alpha and hPPAR gamma dual

positive control 125 99 985 100 hPPAR-gamma positive control > 10000 6 34 100

(-)-b-Peltatin 9 51 9 77

Deoxypodophyllotoxin 9 40 10 66

Podoph llotoxin 13 52 13 64

(-)-b-Peltatin-5-0- b -D-glucopyranoside 60 53 72 67

(+/-)- orelensin 444 38 439 60

(+/-)-Polygamain 647 58 509 69

4'-Demethyldeoxypodophyllotoxin 1211 40 1082 61

Picropodophyllotoxin 1868 46 1771 56

Angeloylpodophyllotoxin 3857 50 > 10000 78

(+/-)-Hermandin > 10000 53 > 10000 73

All publications mentioned in the above specification are herein incorporated by reference. Various modifications and variations of the described methods and system of the present invention will be apparent to those skilled in the art without departing from the scope and spirit of the present invention. Although the present invention has been described in connection with specific preferred embodiments, it should be understood that the invention as claimed should not be unduly limited to such specific embodiments. Indeed, various modifications of the described modes for carrying out the invention which are obvious to those skilled in biochemistry and biotechnology or related fields are intended to be within the scope of the following claims.

Claims

selected from the group consisting of:

e treatment or prevention of a metabolic or chronic inflammatory disorder.

2. A compound for use according to claim 1 wherein the compound is selected from the group consisting of

3. A compound for use according to claim 1 or 2 wherein the disorder is one which is treatable or preventable by modulating the activity of a peroxisome proliferator- activated receptor (PPAR).

4. A compound for use according to any one of claims 1 to 3 wherein the metabolic disorder is selected from the group consisting of insulin resistance, impaired glucose tolerance, impaired fasting glucose and diabetes.

5. A compound for use according to claim 4 wherein the metabolic disorder is type-2 diabetes.

6. A compound for use according to any one of claims 1 to 3 wherein the chronic inflammatory disorder has a genetic or infectious origin.

7. A compound for use according to any one of claims 1 to 3 or 6 wherein the chronic inflammatory disorder is selected from the group consisting of chronic inflammations such as inflammatory bowel disease, Crohn's disease, ulcerative colitis, necrotizing enterocolitis, inflammatory bowel syndrome, liver inflammation, bone inflammation, rheumatoid arthritis, systemic lupus, obesity-associated inflammation and age-related low-grade inflammation.

8. A compound for use according to any preceding claim, wherein the compound is provided as a plant extract.

9. A compound for use according to any preceding claim wherein said compound is a modulator of PPARy and/or PPARa activities.

10. A compound for use according to claim 9 wherein said compound is a modulator of PPARy and PPARa activities.

1 1 . A composition comprising a compound according to claim 1 or 2 for use in accordance with any preceding claim.

12. A composition for use according to claim 1 1 wherein the composition is selected from the group consisting of food products, drinks, pet food products, food additives, nutritional supplements, medical food, and powdered nutritional formulations to be reconstituted in milk or water.

13. A composition for use according to claim 1 1 or 12 to be administered to infants, teenagers, adults, or the elderly.

14. A composition for use according to any one of claims 1 1 to 13 to be administered immediately before or during a meal.