US20080249030A1 - Age Inhibitors - Google Patents

Age Inhibitors Download PDF

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US20080249030A1
US20080249030A1 US11/909,761 US90976106A US2008249030A1 US 20080249030 A1 US20080249030 A1 US 20080249030A1 US 90976106 A US90976106 A US 90976106A US 2008249030 A1 US2008249030 A1 US 2008249030A1
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halogen atoms
dapa
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Pierre Potier
Marie-Claude Denise Michele Zelveyan
Catharine Marie Germaine Magnan
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Definitions

  • the Maillard reaction non-enzymatic glycation, is initiated by the condensation of an amino group present in proteins with a compound containing a carbonyl group, generally a sugar.
  • a multitude of products referred to as “advanced glycation end-products” (AGEs), result from the latter stages of this complex process.
  • AGEs advanced glycation end-products
  • the consequence of the formation of these AGEs is protein cross-linking.
  • Such cross-links have been observed in long-lived proteins such as collagen, lens crystalline, fibronectin, tubulin, myelin, laminin, actin, hemoglobin, albumin and the lipids associated with low-density lipoproteins (LDLs).
  • LDLs low-density lipoproteins
  • AGE-modified proteins increase progressively with age and it is believed that they contribute to the normal tissue remodeling. Moreover, enhanced formation and accumulation of AGEs have been linked to the development of cataracts (Nagaraj et al., J. Biol. Chem. ( 1996) 271, 19338), uraemia (Miyata et al., Kidney Int. (1999) 55, 389), atherosclerosis (Kume et al., Am. J. Pathol. (1995) 147, 654; Stitt et al., Mol. Med. (1997) 3, 617), Alzheimer's disease (Münch et al., Biochem. Soc. Trans.
  • MG methylglyoxal
  • GO glyoxal
  • 3-DG 3-deoxyglucosone
  • MG is the non-enzymatic dephosphorylation of triose-dihydroxyacetone phosphate and glyceraldehyde-3-phosphate, which are glucose metabolites.
  • MG can also be formed by the spontaneous decomposition of triose phosphates or by the metabolism of threonine or acetone.
  • ⁇ -dicarbonyls via glucose auto-oxidation. It is believed that ⁇ -dicarbonyls can be generated during the transformation of a ketoamine, known as the Amadori product, a key intermediate in the Maillard reaction. This ketoamine is itself generated by the transformation of the Schiff-base adduct, which is initially formed during the reaction of glucose with an amine.
  • Lipid peroxidation of polyunsaturated fatty acids also yields reactive carbonyl compounds, such as MG and GO and those characteristic of lipids, such as malondialdehyde (MDA) and 4-hydroxynonenal.
  • MDA malondialdehyde
  • such highly reactive dicarbonyls bind to the amino, guanidine and sulfhydryl groups of proteins and irreversibly form AGEs such as N ⁇ -(1-carboxyethyl)lysine (CEL), N ⁇ -(1-carboxymethyl)lysine (CML), methylglyoxal-derived hydroimidazolone N ⁇ -(5-hydro-5-methyl-4-imidazolon-2-yl)-ornithine (MG-H 1 ), glyoxal-derived hydroimidazolone (G-H 1 ), argpyrimidine, glyoxal-derived lysine dimer, 1,3-di(N ⁇ -lysino)imidazolium salt (GOLD), and methylglyoxal-derived lysine dimer, 1,3-di(N′-lysino)-4-methylimidazolium salt (MOLD).
  • CEL N ⁇
  • Oxidative stress is another factor associated with ageing and with the current criteria for chronic diseases such as diabetes, atherosclerosis and related vascular diseases, rheumatoid polyarthritis and uremia.
  • Oxidative stress is defined as a significant imbalance between antioxidant and oxidant generation systems.
  • An increase in oxidative stress can have a profound effect on the modification of lipoproteins and on transcription, as well as on the functioning and metabolism of cells.
  • Oxidative stress can appear via several mechanisms associated with the overproduction of oxygen radicals, such as the auto-oxidation of glucose and of glycated proteins and the glycation of antioxidant enzymes. Indeed, it has been reported that MG generates reactive oxygen species (ROS) (free radicals) during glycation reactions. Thus, it can be said that oxidative stress and AGE formation are inseparably intertwined.
  • ROS reactive oxygen species
  • the glyoxalase system (glyoxalase I and glyoxalase II) and aldose reductase catalyze the detoxification of these ⁇ -dicarbonyls into D-lactate, glycolate and acetol.
  • a dysfunction of this detoxification metabolism leads to an increase in the quantity of AGEs formed by highly reactive ⁇ -dicarbonyls in the organism.
  • nucleophilic compound AG is a nucleophilic compound with two key reactive functions, namely the nucleophilic hydrazine function —NHNH 2 and the ⁇ -dicarbonyl directing guanidine function —NH—C( ⁇ NH)NH 2 . These two functional groups bound together jointly form a reactive bifunctional scavenger of methylglyoxal, glyoxal and 3-desoxyglucosone (Brownlee, et al., Science (1986) 232, 1629).
  • AG is a well-known selective inhibitor of nitrogen monoxide (NO) and a clinical trial related to the prevention of the progression of diabetic nephropathy by AG was abandoned due to safety concerns (Oturai et al., APMIS (1996) 104, 259; Monnier, V. M. Arch. Biochem. Biophys. (2003) 419, 1).
  • NO nitrogen monoxide
  • Pyridoxamine is another agent able to prevent complications in the diabetic rat with greater effectiveness than that of aminoguanidine, and it is able to scavenge lipid peroxidation products and ⁇ -dicarbonyl compounds (Metz et al., Archives of Biochemistry and Biophysics (2003) 419, 41).
  • Metformin an antihyperglycemic drug widely used in the management of type 2 diabetes, also reduces levels of methylglyoxal and glyoxal both in vivo and in vitro by forming triazepinones (Beisswenger et al., Diabetes Metab. (2003) 29, 6895).
  • carnosine ⁇ -alanyl-L-histidine
  • carnosine ⁇ -alanyl-L-histidine
  • curcumin ⁇ -alanyl-L-histidine
  • NNC39-0028 2,3-diaminophenazine
  • the present inventors have discovered a new class of compounds able to inhibit the formation of advanced glycation end-products by scavenging reactive ⁇ -dicarbonyl compounds.
  • DAPA 2,3-diaminopropionic acid
  • the condensation products would remain in circulation by renal tubular reabsorption mechanisms with the risk of a release ⁇ -dicarbonyls following another metabolic reaction.
  • the compounds discovered by the inventors of the present application can be used as agents, which are more effective than DAPA, to scavenge reactive ⁇ -dicarbonyl compounds such as methylglyoxal, glyoxal and 3-desoxyglucosone by forming adducts which are eliminated in the urine.
  • DAPA prevents the modification of insulin by MG, as is illustrated in FIG. 1 .
  • FIG. 1 FIG.
  • C 1 -C 6 alkyl group means any alkyl group of one to six carbon atoms, linear or branched. In particular, it can relate to a methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl and n-hexyl group.
  • aryl group means one or more aromatic rings of five to eight carbon atoms, possibly adjoining or fused.
  • the aryl group can be a phenyl or naphthyl group, advantageously phenyl.
  • aralkyl group means any aryl group as defined above, linked via an alkyl group as defined above.
  • a benzyl group is an aralkyl group.
  • the “pharmaceutically acceptable addition salt” of a compound means any salt that is pharmaceutically acceptable and that has the desired pharmacological activity of the parent compound.
  • Such salts comprise:
  • Advantageous pharmaceutically acceptable salts are salts formed from hydrochloric acid, trifluoroacetic acid, dibenzoyl-L-tartaric acid and phosphoric acid.
  • references to pharmaceutically acceptable salts include the solvent addition forms (solvates) or the crystalline forms (polymorphs), as defined herein, of the given acid addition salt.
  • the stereochemistry of the C-1 position of formula I (the carbon atom at the junction of the NH 2 and X groups) can be R or S or a mixture thereof.
  • the stereochemistry of the C-2 position (the carbon atom at the junction of the NH 2 and R 2 groups) can be R or S or a mixture thereof.
  • amino acids means all natural ⁇ -amino acid residues (for example alanine (Ala), arginine (Arg), asparagine (Asn), aspartic acid (Asp), cysteine (Cys), glutamine (Gln), glutamic acid (Glu), glycine (Gly), histidine (His), isoleucine (Ile), leucine (Leu), lysine (Lys), methionine (Met), phenylalanine (Phe), proline (Pro), serine (Ser), threonine (Thr), tryptophane (Trp), tyrosine (Tyr) and valine (Val)) in D or L form, as well as non-natural amino acids (for example, ⁇ -alanine, allylglycine, tert-leucine, norleucine (Nle), 3-amino-adipic acid, 2-aminobenzoic acid, 3-
  • the term also includes natural and non-natural amino acids carrying a conventional amino protecting group (for example, an acetyl group, tert-butyloxycarbonyl, benzyloxycarbonyl or 9-fluorenylmethylcarbonyl), as well as natural and non-natural amino acids protected at the carboxylic end (advantageously by a C 1 -C 18 alkyl group, an ester, a phenyl amide or benzyl amide or an amide, which, respectively, give a carboxylic end of the following formula: —CO(C 1 -C 18 alkyl), —COO (C 1 -C 18 alkyl), —CONHphenyl, CONHbenzyl, or CONH 2 ).
  • the amino acid according to the present invention has its carboxylic end unprotected.
  • the amino acid according to the present invention has its carboxylic end protected in the form of a C 1 -C 18 alkyl ester (—COO(C 1 -C 18 alkyl)), preferably a C 13 -C 18 alkyl ester (—COO(C 13 -C 18 alkyl)).
  • the amino acid is linked to the X radical of the compound of formula I by the N-terminal end.
  • the bond thus formed is as follows: —X—NH—R, wherein R represents the remainder of the amino acid molecule.
  • the amino acid according to the present invention is substituted by one or more halogen atoms (Br, Cl, I or F), advantageously fluorine, or one or more CF 3 groups.
  • this substitution is present on the alkyl or aryl moiety of the amino acid. Even more advantageously, the nitrogen atom is not substituted.
  • the principal advantages of substitution by a halogen atom, in particular by a fluorine atom, or by a CF 3 group relate to the bioavailability of the compounds obtained and, in particular, to improvements in their cell membrane permeation and binding characteristics.
  • the amino acid is selected among alanine, valine, isoleucine, proline, leucine, phenylalanine, glycine, ⁇ -alanine, norleucine, aspartic acid, lysine, or tert-leucine, advantageously among alanine, valine, isoleucine, proline, phenylalanine, leucine, norleucine or tert-leucine.
  • the phenyl radical of phenylalanine is substituted by one or more halogen atoms, advantageously fluorine, or by one or more CF 3 groups, advantageously in the para position, less advantageously in the ortho or meta position.
  • the butyl radical of norleucine is substituted by one or more halogen atoms, advantageously fluorine, or by one or more CF 3 groups.
  • C 1 -C 18 alkyl group means any alkyl group of one to 18 carbon atoms, linear or branched. In particular, it can relate to a methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl and n-hexyl group.
  • the term “peptide comprising two amino acids” means any sequence of two amino acids as defined below or of peptidyl residues.
  • the sequence can be linear or cyclic.
  • a cyclic peptide can be prepared or can result from the formation of a disulfide bridge between two cysteine residues in a sequence.
  • the peptide is linked to the remainder of the compound of formula I by the N-terminal end.
  • Peptide derivatives can be prepared by any conventional method (in solution or solid phase) known in the art, such as those described in the examples below.
  • the peptide sequences specifically described in the present application are written with the amino end on the left and the carboxylic end on the right.
  • the peptide is selected among Ala-Gly, Ala-Ala, Ala-Pro or Ala-Val, advantageously among L-Ala-Gly, L-Ala-L-Ala, L-Ala-L-Pro or L-Ala-L-Val.
  • the compound according to the present invention is such that X represents C ⁇ O, CH 2 or C ⁇ S.
  • the compound according to the present invention is such that R 2 represents H or XR 1 , advantageously XR 1 .
  • the compound according to the present invention is such that R, represents an amino acid, advantageously selected among alanine, valine, isoleucine, proline, leucine, norleucine, phenylalanine or tert-leucine.
  • C 1 -C 12 alkyl group means any alkyl group of one to 12 carbon atoms, linear or branched. In particular, it can relate to a methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl and n-hexyl group.
  • C 1 -C 30 alkoxy means any —O—R radical, wherein R is a C 1 -C 30 alkyl radical as defined herein.
  • alkoxy radicals include, but are not limited to, methoxy, ethoxy, isopropoxy and the like.
  • R 2 ⁇ H or COR 1 .
  • the compound according to the present invention is selected among:
  • the present invention also relates to the use of a compound according to the present invention to prevent the deterioration of proteins in foods.
  • Said foods can be of animal or plant origin.
  • the compounds according to the present invention are administered in an effective quantity in said foods in order to prevent the deterioration and the degradation of proteins contained therein. Such a use increases the period during which the foods can be consumed and stored and preserves their nutritional and organoleptic qualities.
  • the present invention relates to a pharmaceutical or cosmetic composition
  • a pharmaceutical or cosmetic composition comprising a compound according to the present invention and a pharmaceutically or cosmetically acceptable excipient.
  • the present invention relates to a compound of following general formula I
  • the compound according to the present invention for use as a drug is represented by the following general formula II:
  • the compound according to the present invention for use as a drug is selected among
  • the drug according to the present invention is a scavenger of reactive carbonyl compounds, advantageously an inhibitor of the formation of advanced glycation end-products.
  • the drug according to the present invention is for the prevention and/or the treatment of a state or disease due to the formation of advanced glycation end-products or to the cross-linking of proteins, for the prevention and/or the treatment of the deleterious effects of the ageing of an organism, said effects being the formation of advanced glycation end-products or the cross-linking of proteins, or in a patient for the slowing or the stopping of the progression of complications resulting from diabetes, said complications resulting from the formation of advanced glycation end-products or from the cross-linking of proteins.
  • the drug according to the present invention is intended to treat, prevent and/or slow in a patient the progression of diseases chosen among rheumatoid polyarthritis, Alzheimer's disease, uremia, neurodegenerative diseases, atherosclerosis, microvascular and macrovascular complications of diabetes including diabetic retinopathy and renal failure due to diabetic nephropathy, microangiopathies and macroangiopathies, cataracts, amyloidosis associated with dialysis or with Alzheimer's disease, Parkinson's disease, gingivitis, cavities, bucco-dental conditions, diabetic ulcers, chronic renal failure, chronic renal dialysis, inflammatory diseases, age-related rheumatic disorders and porphyria and to treat early-stage cancers.
  • diseases chosen among rheumatoid polyarthritis, Alzheimer's disease, uremia, neurodegenerative diseases, atherosclerosis, microvascular and macrovascular complications of diabetes including diabetic retinopathy and renal failure due to diabetic nephropathy, microangiopathies and macro
  • the drug according to the present invention is for administration by oral route.
  • the present invention relates to the use of a compound of general formula I or II as defined above for the preparation of a drug that scavenges reactive carbonyl compounds, advantageously an inhibitor of the formation of advanced glycation end-products, advantageously for
  • the prevention and/or the treatment of a state or disease due to the formation of advanced glycation end-products or to the cross-linking of proteins the prevention and/or the treatment of the deleterious effects of the ageing of an organism, said effects being the formation of advanced glycation end-products or the cross-linking of proteins, or in a patient for the slowing or the stopping of the progression of complications resulting from diabetes, said complications resulting from the formation of advanced glycation end-products or from the cross-linking of proteins;
  • rheumatoid polyarthritis Alzheimer's disease, uremia, neurodegenerative diseases, atherosclerosis, microvascular and macrovascular complications of diabetes including diabetic retinopathy and renal failure due to diabetic nephropathy, microangiopathies and macroangiopathies, cataracts, amyloidosis associated with dialysis or with Alzheimer's disease, Parkinson's disease, gingivitis, cavities, bucco-dental conditions, diabetic ulcers, chronic renal failure, chronic renal dialysis, inflammatory diseases, age-related rheumatic disorders and porphyria and to treat early-stage cancers.
  • diseases chosen among rheumatoid polyarthritis, Alzheimer's disease, uremia, neurodegenerative diseases, atherosclerosis, microvascular and macrovascular complications of diabetes including diabetic retinopathy and renal failure due to diabetic nephropathy, microangiopathies and macroangiopathies, cataracts, amyloidosis associated with dialysis or with Alzheimer's disease, Parkinson'
  • the present invention also relates to a method for the prevention and/or the treatment of a state or disease due to the formation of advanced glycation end-products or to the cross-linking of proteins, the prevention and/or the treatment of the deleterious effects of the ageing of an organism, said effects being the formation of advanced glycation end-products or the cross-linking of proteins, or in a patient for the slowing or the stopping of the progression of complications resulting from diabetes, said complications resulting from the formation of advanced glycation end-products or from the cross-linking of proteins; for the treatment, prevention and/or slowing in a patient of the progression of diseases chosen among rheumatoid polyarthritis, Alzheimer's disease, uremia, neurodegenerative diseases, atherosclerosis, microvascular and macrovascular complications of diabetes including diabetic retinopathy and renal failure due to diabetic nephropathy, microangiopathies and macroangiopathies, cataracts, amyloidosis associated with dialysis or with
  • the present invention relates to a drug or a pharmaceutical composition comprising a compound according to the present invention.
  • compositions or drugs can be formulated for administration in mammals, including human being. Dosing varies according to the treatment and to the affection to be treated. Said compositions or drugs are provided in such a way as to be suitable for administration by the digestive or parenteral route.
  • the active ingredient can be administered in unit dose forms, in a mixture with conventional pharmaceutical carriers, to animals or to humans.
  • Suitable unit dose forms include forms for oral administration such as tablets, gelatin capsules, powders, granules and oral solutions or suspensions, sublingual and buccal administration forms, subcutaneous, intramuscular, intravenous, intranasal, intraocular, or rectal administration forms.
  • the principal active ingredient is mixed with a pharmaceutical carrier such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic or analogues.
  • a pharmaceutical carrier such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic or analogues.
  • the tablets can be coated with sucrose or other suitable materials or the tablets can be treated so that they have extended or delayed activity and that they continuously release a predetermined quantity of the active ingredient.
  • a preparation in gelatin capsules is obtained by mixing the active ingredient with a diluent and by pouring the mixture obtained into soft or hard gelatin capsules.
  • a preparation in syrup or elixir form can contain the active ingredient along with a sweetener and an antiseptic, as well as a flavoring agent and an agent that provides a suitable color.
  • Water-dispersible powders or granules can contain the active ingredient in a mixture with dispersion, wetting or suspension agents, as well as with flavor correctors or sweeteners.
  • Suppositories which are prepared with binders that melt at rectal temperature, such as cocoa butter or polyethylene glycol, are used for rectal administration.
  • suitable preparations include aqueous suspensions, isotonic saline solutions or sterile injectable solutions containing pharmacologically compatible dispersion and/or wetting agents.
  • the active ingredient can be also formulated in microcapsule form, optionally with one or more carrier additives.
  • the active ingredient can also be administered by topical route.
  • the present invention also relates to the cosmetic use of a compound according to the present invention as an anti-ageing and restructuring active ingredient for the epidermis and the papillary dermis and/or as an anti-wrinkle active ingredient.
  • the compounds according to the present invention have a tensor effect on the skin. They can be administered by oral or topical route.
  • the cosmetic or pharmaceutical compositions according to the present invention can be formulated for administration by topical route. They can be provided in the forms commonly used for this type of administration, i.e., notably lotions, foams, gels, dispersions, sprays, shampoos, serums, masks, body milks or creams, for example, with excipients enabling in particular cutaneous penetration in order to improve the properties and the accessibility of the active ingredient.
  • the forms can be a single-phase vehicle comprised of a neutral hydroxypropylcellulose gel or a gel containing sodium carboxymethylcellulose. It is also possible to prepare creams and two-phase vehicles containing a hydrophilic phase dispersed in a lipophilic phase.
  • compositions or drugs generally contain a physiologically acceptable medium, in general containing water or solvents such as alcohols, ethers or glycols, for example. They can also contain a cosmetically or pharmaceutically acceptable excipient.
  • excipients can be selected among compounds exhibiting suitable compatibility with the active ingredient. Examples of such excipients include natural water-soluble polymers such as polysaccharides (xanthan gum, carob bean gum, peptin, etc.) or polypeptides, cellulose derivatives such as methylcellulose, hydroxypropylcellulose and hydroxypropyl-methylcellulose, as well as synthetic polymers, poloxamers, carbomers, PVA or PVP.
  • composition can also contain surfactants, stabilizers, emulsifiers, thickeners, other active ingredients providing a complementary or possibly synergistic effect, trace elements, essential oils, fragrances, colorants, collagen, chemical or mineral filters, hydrating agents or thermal spring water.
  • the present invention also relates to a method for the cosmetic anti-ageing treatment of the skin by the application of a composition comprising a compound according to the present invention.
  • DAPA 2,3-diaminopropionic acid
  • DABA 2,3-diaminobutylic acid (absent specification to the contrary) or 2,4-diaminobutylic acid
  • DASA diaminosuccinic acid
  • EDC 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride
  • HOBt 1-hydroxybenzotriazole hydrate
  • Boc t-butoxycarbonyl
  • TFA trifluoroacetic acid
  • THF tetrahydrofuran.
  • FIG. 1 presents the comparative effects of dicarbonyl scavengers in the form of dihydrochloride according to the present invention and the comparison with DAPA on the modification of insulin (Ins) by methylglyoxal (MG). The percentage of insulin is indicated following incubation with methylglyoxal in the presence or absence of dicarbonyl scavengers. Insulin (0.034 mM) is incubated in vitro in a 10 mM phosphate buffer, pH 7.45 (containing 0.1 M NaCl) with methylglyoxal (3.4 mM) in the presence of dicarbonyl scavengers (4.08 mM) for 21 hours at 37° C. Insulin concentration is measured by HPLC (same conditions as in FIG. 3 ).
  • FIG. 2 presents the comparative effects of the dicarbonyl scavengers of the prior art on the modification of insulin by methylglyoxal.
  • the experimental conditions are identical to those described in FIG. 1 .
  • the compounds marked with an asterisk (*) are used in hydrochloride form.
  • FIG. 3 presents the results obtained by HPLC for two compounds according to the present invention, L-DAPA-L-Leu (example 1) and L-DAPA-L-Val (example 23), on insulin modifications induced by methylglyoxal. It can be observed that these modifications are prevented.
  • the HPLC conditions are as follows: C-18, Symmetry 300 (4.6 ⁇ 250 mm) column, injection volume 100 ⁇ l of reaction mixture; flow 1 ml/min; temperature 40° C.; solvent A: H 2 O+0.1% TFA; solvent B: 60/40 CH 3 CN/H 2 O+0.1% TFA; linear gradient of 50% B to 55% B in 15 minutes; detection: TV at 215 nm: PDA (chromatograms extracted at 220 nm).
  • FIG. 4 presents the results obtained by HPLC for two compounds according to the present invention, L-DAPA-L-Leu (example 1) and L-DAPA-L-Val (example 23), on somatostatin-14 modifications induced by methylglyoxal.
  • HPLC conditions are as follows: C-18, Symmetry 300 (4.6 ⁇ 250 mm) column, injection volume 100 ⁇ l of reaction mixture; flow 1 ml/min; solvent A: H 2 O+0.1% TFA; solvent B: 80/20 CH 3 CN/H 2 O+0.1% TFA; linear gradient: from 20% B to 60% B in 15 minutes and isocratic from 60% B for 10 minutes; ambient temperature; detection: PDA (chromatograms extracted at 215 nm).
  • the compounds according to the present invention prevent the modifications induced by methylglyoxal.
  • (a) represents the results of somatostatin-14 alone;
  • (b) represents the results of somatostatin-14+methylglyoxal;
  • (c) represents the results of somatostatin-14+methylglyoxal+L-DAPA-L-Val (example 23) and
  • (d) represents the results of somatostatin-14+methylglyoxal+L-DAPA-L-Leu (example 1).
  • somatostatin-14 (0.03 mm) is incubated in vitro in a 10 mM phosphate buffer, pH 7.45, containing 0.1 M NaCl, with or without (a) methylglyoxal (3.6 mM) in the presence ((c) and (d)) or the absence (b) of compounds according to the present invention (4.3 mM) for 24 hours at 37° C.
  • FIG. 5 presents the results obtained by HPLC for three compounds according to the present invention, L-DAPA-L-Ile (example 18), L-DAPA-L-Val (example 23) and L-DAPA-L-Leu (example 1), on RNase A modifications induced by methylglyoxal.
  • HPLC conditions are as follows: C-18, Symmetry 300 (4.6 ⁇ 250 mm) column, injection volume 100 ⁇ l of reaction mixture diluted to 1/10; flow 1 ml/min; temperature 40° C.; solvent A: H 2 O+0.1% TFA; solvent B: 60/40 CH 3 CN/H 2 O+0.1% TFA; linear gradient of 206 B to 80% B in 20 minutes; detection: UV at 215 nm: PDA (chromatograms extracted at 215 nm).
  • the compounds according to the present invention prevent the modifications to RNase A.
  • (a) represents the results of RNase A;
  • (b) represents the results of RNase A+methylglyoxal;
  • (c) represents the results of RNase A+methylglyoxal+L-DAPA-L-Ile (example 18);
  • (d) represents the results of RNase A+methylglyoxal+L-DAPA-L-Val (example 23);
  • (e) represents the results of RNase A+methylglyoxal+L-DAPA-L-Leu (example 1).
  • RNase A (0.08 mM) is incubated in vitro in a 100 mM phosphate buffer, pH 7.45, with or without (a) methylglyoxal (32 mM) in the presence ((c), (d) and (e)) or the absence (b) of compounds according to the present invention (38 mM) for 21 hours at 37° C.
  • FIGS. 6 and 7 represents EA endothelial cell growth in the presence of compounds according to the present invention and compounds according to the prior art, in particular aminoguanidine (AG) and diaminopropionic acid (DAPA), in the presence or absence of methylglyoxal (MG).
  • AG aminoguanidine
  • DAPA diaminopropionic acid
  • the general method for producing compounds according to the present invention comprises step (a), or steps (a) and (b), or steps (a), (b) and (c), or steps (a) and (d), or steps (a), (d) and (e), as follows:
  • an amino acid or peptide alkyl ester with an N-protected diamino acid (for example, DAPA, DABA, DASA, Orn or Lys according to the value of n) in an organic solvent, advantageously dichloromethane, advantageously by using reagents forming an active ester, such as EDC and HOBt, for example, advantageously under agitation at room temperature;
  • step (b) alkaline hydrolysis of the alkyl ester obtained in step (a), advantageously with LiOH, advantageously in the solvent THF/MeOH/H 2 O, MeOH/H 2 O or H 2 O, then acidification, advantageously with an aqueous solution of KHSO 4 at pH 5 to obtain the pure acid;
  • step (b) deprotection of the N-protecting groups of the acid obtained in step (b) advantageously with 3 M HCl-dioxane (or THF) and elimination of the volatile components;
  • step (a) preparation of thioamides by addition of Lawesson's reagent to the peptide obtained in step (a), advantageously under inert atmosphere, and heating, advantageously at 80° C., for two hours;
  • step (d) deprotection of the thioamides with di-Boc, tert-butyl ester protection obtained in step (d) by the addition of TFA in an organic solvent, advantageously dichloromethane, at a low temperature, advantageously 0° C.
  • organic solvent advantageously dichloromethane
  • the compounds according to the present invention can be produced according to the method described hereafter, i.e., the implementation of step (1), or of steps (1) and (2), or of steps (1), (2) and (3), or of steps (1) and (4), or of steps (1), (4) and (5).
  • a diamino acid for example, DAPA, DABA, DASA, Orn or Lys
  • a diamino acid for example, DAPA, DABA, DASA, Orn or Lys
  • an amino acid alkyl ester 1.1 mmol
  • dichloromethane 5.0 ml
  • reagents forming an active ester for example, EDC (1.2 mmol) and HOBt (1.1 mmol)
  • EDC 1.2 mmol
  • HOBt 1.1 mmol
  • alkyl ester 1.0 mmol
  • MeOH/H 2 O MeOH/H 2 O
  • an alkaline solution preferably 1.0 mmol LiOH
  • the reaction mixture was then agitated until all of the starting ester had disappeared (approximately overnight).
  • the reaction mixture was acidified with an aqueous solution of KHSO4 at pH 5 and then extracted with an organic solvent (preferably CH 2 Cl 2 ).
  • the organic phase was dried (Na 2 SO 4 ) and then evaporated under reduced pressure to obtain the crude acid, which is used directly in the following reaction without additional purification.
  • Lawesson's reagent (1.1 mmol) was added all at once to a solution of the dipeptide mentioned above (step 1) (2.0 mmol) in toluene (10 ml) at room temperature under an argon atmosphere. The reaction mixture was agitated for two hours at 80° C. The solvent was eliminated by evaporation under reduced pressure. The residue was purified by silica-gel column chromatography (CH 2 C 12 then 10/1 CH 2 C 12 /Et 2 O) to obtain the corresponding thioamide.
  • insulin is incubated with methylglyoxal in the presence of an equimolar quantity of the AGE inhibitors according to the present invention under physiological conditions. After 24 hours, the modification of insulin by MG is considerably reduced, as is illustrated in FIG. 1 .
  • FIG. 2 illustrates the effectiveness of certain known reactive dicarbonyl scavengers in inhibiting the modification of insulin by MG.
  • Ribonuclease A and lysozyme (10 mg/ml) are incubated in the presence of methylglyoxal (10 mM) or in the presence of methylglyoxal and one of the inhibitors according to the present invention in an equimolar quantity at 37° C. After 48 hours of incubation, the proteins are analyzed by polyacrilamide gel electrophoresis (8%-16% SDS PAGE gel).
  • inhibitors according to the present invention namely L-DAPA-L-Leu (example 1), L-DAPA-L-Ile (example 18), L-DAPA-L-Val (example 23), D-DAPA-D-Ala (example 8), (2S,3S)-DASA-L-Leu (example 29), L-DAPA-L-Gly (example 17) or L-DABA-L-Leu (example 12), provides protection from these structural modifications caused by methylglyoxal.
  • the presence of inhibitors according to the present invention largely prevents the formation of cross-linked proteins by scavenging methylglyoxal.
  • the enzymatic activity of ribonuclease A after treatment with methylglyoxal and the various inhibitors according to the present invention is measured using the methylene blue RNA staining technique of Greiner-Stöffele et al. (Anal. Biochem. (1996) 240, 24).
  • Enzyme kinetics as measured by spectrophotometry at 688 nm show that the inhibition of enzymatic activity caused by methylglyoxal is considerably reduced in the presence of the inhibitors according to the present invention.
  • MG reacts with a protein,s lysine and arginine residues, thus altering the charges on the modified polypeptide. This was demonstrated by the electrophoresis of glyoxalase I treated with MG under non-denaturing conditions.
  • the exposure of glyoxalase I to MG (10 mM) for 24 hours increases the mobility of the protein toward the positive electrode, a change that is consistent with the loss of positive charges from the ⁇ -amino and guanidino groups and the gain of negative charges.
  • the inhibitors according to the present invention L-DAPA-L-Leu (example 1) or L-DAPA-L-Ile (example 18) are included in the incubation mixture, the presence of these compounds inhibits the gain of negative charge.
  • glyoxalase I a key protein in the ⁇ -oxoaldehyde detoxification system
  • methylglyoxal modifies the protein. This modification causes a change in charge and a 50% decrease in enzymatic activity compared to the control.
  • the cells used for the test are from the EA.hy 926 cell line, which are endothelial cells obtained by the hybridization of human umbilical vein endothelial cells (HUVECs) with lung cancer cells (A549).
  • the EA.hy 926 endothelial cells are incubated in Dulbecco's modified Eagle's Medium (DMEM) enriched with 10% fetal calf serum.
  • DMEM Dulbecco's modified Eagle's Medium
  • the cells are incubated in 12-well plates. Each well initially contains 100,000 cells. Cell growth is achieved by incubating the cells in 2 ml of culture medium after adding or not adding the various potential inhibitors (1 mM) and/or methylglyoxal (600 ⁇ M) for 48 hours at 37° C. in a moist atmosphere with 5% CO 2 .
  • the number of cells is evaluated in the following way:
  • the cells are stained using the (4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay.
  • MTT penetrates in the cell where it is converted into formazan.
  • the quantity of formazan formed is proportional to the number of living cells.
  • the results are expressed as a relative percentage of the number of cells after treatment compared to the number of control cells without treatment [100*OD (treated cells)/OD(control cells)]. Detection is carried out by UV/visible spectrophotometry at 570 nm.
  • MTT (yellow) penetrates the cell and is converted into an insoluble blue compound, formazan, by cleavage of its tetrazolium rings by the mitochondrial dehydrogenase enzymes of living cells.
  • Formazan is solubilized by isopropanol.
  • the number of cells is proportional to the quantity of formazan formed and its absorbance.
  • methylglyoxal suppresses cell growth.
  • aminoguanidine a known MG scavenger
  • suppresses this process in a spectacular manner The same trend can be observed with the compounds according to the present invention, in particular L-DAPA-L-Val (example 23), L-DAPA-L-Leu (example 1) and L-DAPA-L-Ile (example 18).
  • Other known MG scavengers such as carnosine and metformin, proved less effective in this test. Additional examples of the inhibiting effect of the compounds according to the present invention compared to the suppression of cell growth by MG are illustrated in FIG. 7 .
  • L-DAPA, (2S,3S)-DASA and D-DAPA, as well as HCl and TFA salts, are found in toxic and nontoxic products. It can be noted that the non-toxicity of the compounds increases their MG-scavenging activity compared to cells growing with MG alone. The difference between the relative values of the number of cells growing with the analyzed compound and the cells growing in the presence of MG and the analyzed compound makes it possible to evaluate the product's role as a MG scavenger.
  • Eight compounds according to the present invention possess this activity in particular, namely L-DAPA-L-Val.2HCl ( ⁇ 3) (example 23), L-DAPA-L-Leu.2HCl ( ⁇ 13) (example 1), L-DAPA-L-Ile.2HCl ( ⁇ 9) (example 18), (2S,3S)-DASA-L-Val.2HCl ( ⁇ 15) (example 29), L-DAPA-L-Leu.2TFA ( ⁇ 18) (example 3), L-DABA-L-Leu.2HCl ( ⁇ 4) (example 12) and L-DAPA-L-Phe,.2HCl ( ⁇ 6) (example 21).

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CA2603386A1 (fr) 2006-10-05
JP2008534557A (ja) 2008-08-28
FR2883873A1 (fr) 2006-10-06
FR2883873B1 (fr) 2009-07-10
GEP20104882B (en) 2010-01-11
MX2007012238A (es) 2008-03-18
KR20080006557A (ko) 2008-01-16
AU2006228163A1 (en) 2006-10-05
KR101343929B1 (ko) 2013-12-24
ZA200708835B (en) 2009-09-30
EP1863832B1 (de) 2012-01-04
CA2603386C (fr) 2018-03-06
KR101536839B1 (ko) 2015-07-14
BRPI0609783A8 (pt) 2018-03-13
CN101268093A (zh) 2008-09-17
WO2006103274A8 (fr) 2007-05-03
KR20130110222A (ko) 2013-10-08
US20120252866A1 (en) 2012-10-04
EA200702104A1 (ru) 2008-02-28
CN101268093B (zh) 2013-04-03
MA29416B1 (fr) 2008-04-01
US9512176B2 (en) 2016-12-06
JP4695186B2 (ja) 2011-06-08
BRPI0609783A2 (pt) 2011-10-11

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