WO2004071416A2 - Novel inhibitors of formation of advanced glycation endproducts (ages) - Google Patents
Novel inhibitors of formation of advanced glycation endproducts (ages) Download PDFInfo
- Publication number
- WO2004071416A2 WO2004071416A2 PCT/US2004/003203 US2004003203W WO2004071416A2 WO 2004071416 A2 WO2004071416 A2 WO 2004071416A2 US 2004003203 W US2004003203 W US 2004003203W WO 2004071416 A2 WO2004071416 A2 WO 2004071416A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- lrl
- acid
- chlorobenzyl
- compound
- fluoro
- Prior art date
Links
- 230000015572 biosynthetic process Effects 0.000 title claims description 54
- 108010005094 Advanced Glycation End Products Proteins 0.000 title description 41
- 239000003112 inhibitor Substances 0.000 title description 39
- 150000001875 compounds Chemical class 0.000 claims abstract description 98
- 108090000623 proteins and genes Proteins 0.000 claims abstract description 56
- 102000004169 proteins and genes Human genes 0.000 claims abstract description 56
- 230000036252 glycation Effects 0.000 claims abstract description 53
- 238000004132 cross linking Methods 0.000 claims abstract description 32
- 206010012601 diabetes mellitus Diseases 0.000 claims abstract description 28
- 238000000034 method Methods 0.000 claims abstract description 24
- 230000000694 effects Effects 0.000 claims abstract description 13
- 230000032683 aging Effects 0.000 claims abstract description 11
- 239000007795 chemical reaction product Substances 0.000 claims abstract description 6
- 230000002401 inhibitory effect Effects 0.000 claims description 15
- -1 [(methyleneoxyethyleneamino) phenoxy] isobutyric acid Chemical class 0.000 claims description 14
- 239000002253 acid Substances 0.000 claims description 14
- 201000001320 Atherosclerosis Diseases 0.000 claims description 8
- PSWSDQRXCOJSFC-FJXQXJEOSA-N (2s)-2-acetamido-3-(1h-imidazol-5-yl)propanoic acid;hydrate Chemical compound O.CC(=O)N[C@H](C(O)=O)CC1=CN=CN1 PSWSDQRXCOJSFC-FJXQXJEOSA-N 0.000 claims description 7
- QMLIPLVKAAOHEE-UHFFFAOYSA-N 2-[4-(carbamoylamino)phenoxy]-2-methylpropanoic acid Chemical compound OC(=O)C(C)(C)OC1=CC=C(NC(N)=O)C=C1 QMLIPLVKAAOHEE-UHFFFAOYSA-N 0.000 claims description 7
- PNKYIZBUGAZUHQ-UHFFFAOYSA-N 2-quinolin-8-yloxyacetic acid Chemical compound C1=CN=C2C(OCC(=O)O)=CC=CC2=C1 PNKYIZBUGAZUHQ-UHFFFAOYSA-N 0.000 claims description 7
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 claims description 7
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 claims description 7
- 208000024827 Alzheimer disease Diseases 0.000 claims description 5
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 5
- 206010029350 Neurotoxicity Diseases 0.000 claims description 3
- 206010044221 Toxic encephalopathy Diseases 0.000 claims description 3
- 230000007135 neurotoxicity Effects 0.000 claims description 3
- 231100000228 neurotoxicity Toxicity 0.000 claims description 3
- 208000037157 Azotemia Diseases 0.000 claims description 2
- 230000002939 deleterious effect Effects 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- 208000009852 uremia Diseases 0.000 claims description 2
- 150000003839 salts Chemical class 0.000 claims 7
- 239000003937 drug carrier Substances 0.000 claims 1
- 239000008194 pharmaceutical composition Substances 0.000 claims 1
- 235000000346 sugar Nutrition 0.000 abstract description 11
- 230000008569 process Effects 0.000 abstract description 10
- 210000004369 blood Anatomy 0.000 abstract description 9
- 239000008280 blood Substances 0.000 abstract description 9
- 150000008163 sugars Chemical class 0.000 abstract description 9
- 230000004048 modification Effects 0.000 abstract description 6
- 238000012986 modification Methods 0.000 abstract description 6
- 206010063493 Premature ageing Diseases 0.000 abstract description 3
- 208000032038 Premature aging Diseases 0.000 abstract description 3
- 238000002845 discoloration Methods 0.000 abstract description 3
- 235000013305 food Nutrition 0.000 abstract description 3
- 230000003834 intracellular effect Effects 0.000 abstract description 3
- AIJULSRZWUXGPQ-UHFFFAOYSA-N Methylglyoxal Chemical compound CC(=O)C=O AIJULSRZWUXGPQ-UHFFFAOYSA-N 0.000 description 28
- HAMNKKUPIHEESI-UHFFFAOYSA-N aminoguanidine Chemical compound NNC(N)=N HAMNKKUPIHEESI-UHFFFAOYSA-N 0.000 description 24
- 238000003556 assay Methods 0.000 description 21
- 238000006243 chemical reaction Methods 0.000 description 19
- 239000000047 product Substances 0.000 description 19
- 230000005764 inhibitory process Effects 0.000 description 14
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 10
- 239000008103 glucose Substances 0.000 description 10
- PYMYPHUHKUWMLA-LMVFSUKVSA-N Ribose Natural products OC[C@@H](O)[C@@H](O)[C@@H](O)C=O PYMYPHUHKUWMLA-LMVFSUKVSA-N 0.000 description 9
- HMFHBZSHGGEWLO-UHFFFAOYSA-N alpha-D-Furanose-Ribose Natural products OCC1OC(O)C(O)C1O HMFHBZSHGGEWLO-UHFFFAOYSA-N 0.000 description 9
- 239000000543 intermediate Substances 0.000 description 9
- 230000007246 mechanism Effects 0.000 description 9
- 210000001519 tissue Anatomy 0.000 description 9
- HMFHBZSHGGEWLO-SOOFDHNKSA-N D-ribofuranose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H]1O HMFHBZSHGGEWLO-SOOFDHNKSA-N 0.000 description 8
- 208000002249 Diabetes Complications Diseases 0.000 description 8
- 206010012655 Diabetic complications Diseases 0.000 description 8
- WGCNASOHLSPBMP-UHFFFAOYSA-N Glycolaldehyde Chemical compound OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 8
- 238000011161 development Methods 0.000 description 8
- 230000018109 developmental process Effects 0.000 description 8
- 125000004989 dicarbonyl group Chemical group 0.000 description 8
- LEQAOMBKQFMDFZ-UHFFFAOYSA-N glyoxal Chemical compound O=CC=O LEQAOMBKQFMDFZ-UHFFFAOYSA-N 0.000 description 8
- 238000001727 in vivo Methods 0.000 description 8
- 150000002632 lipids Chemical class 0.000 description 8
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 7
- 238000009825 accumulation Methods 0.000 description 7
- 239000003795 chemical substances by application Substances 0.000 description 7
- 238000000338 in vitro Methods 0.000 description 7
- 238000011534 incubation Methods 0.000 description 7
- 210000003734 kidney Anatomy 0.000 description 7
- 239000003642 reactive oxygen metabolite Substances 0.000 description 7
- 102000008186 Collagen Human genes 0.000 description 6
- 108010035532 Collagen Proteins 0.000 description 6
- 241000700159 Rattus Species 0.000 description 6
- 229920001436 collagen Polymers 0.000 description 6
- 201000001421 hyperglycemia Diseases 0.000 description 6
- 108090000765 processed proteins & peptides Proteins 0.000 description 6
- 230000002000 scavenging effect Effects 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- 230000000451 tissue damage Effects 0.000 description 6
- 231100000827 tissue damage Toxicity 0.000 description 6
- RRUYWEMUWIRRNB-LURJTMIESA-N (2s)-6-amino-2-[carboxy(methyl)amino]hexanoic acid Chemical compound OC(=O)N(C)[C@H](C(O)=O)CCCCN RRUYWEMUWIRRNB-LURJTMIESA-N 0.000 description 5
- 102000001554 Hemoglobins Human genes 0.000 description 5
- 108010054147 Hemoglobins Proteins 0.000 description 5
- 102000007330 LDL Lipoproteins Human genes 0.000 description 5
- 108010007622 LDL Lipoproteins Proteins 0.000 description 5
- 235000010323 ascorbic acid Nutrition 0.000 description 5
- 229960005070 ascorbic acid Drugs 0.000 description 5
- 239000011668 ascorbic acid Substances 0.000 description 5
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 5
- 230000006870 function Effects 0.000 description 5
- JVJFIQYAHPMBBX-UHFFFAOYSA-N 4-hydroxynonenal Chemical compound CCCCCC(O)C=CC=O JVJFIQYAHPMBBX-UHFFFAOYSA-N 0.000 description 4
- WSMYVTOQOOLQHP-UHFFFAOYSA-N Malondialdehyde Chemical compound O=CCC=O WSMYVTOQOOLQHP-UHFFFAOYSA-N 0.000 description 4
- MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical compound O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 description 4
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 4
- 125000003277 amino group Chemical group 0.000 description 4
- 125000003118 aryl group Chemical group 0.000 description 4
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 4
- 238000011156 evaluation Methods 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 229940015043 glyoxal Drugs 0.000 description 4
- 229940118019 malondialdehyde Drugs 0.000 description 4
- 230000001404 mediated effect Effects 0.000 description 4
- 230000008506 pathogenesis Effects 0.000 description 4
- 239000002953 phosphate buffered saline Substances 0.000 description 4
- 230000002265 prevention Effects 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 3
- 208000020832 chronic kidney disease Diseases 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 229940000406 drug candidate Drugs 0.000 description 3
- 201000000523 end stage renal failure Diseases 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 230000002427 irreversible effect Effects 0.000 description 3
- 102000035118 modified proteins Human genes 0.000 description 3
- 108091005573 modified proteins Proteins 0.000 description 3
- AYEKKSTZQYEZPU-RYUDHWBXSA-N pentosidine Chemical compound OC(=O)[C@@H](N)CCCCN1C=CC=C2N=C(NCCC[C@H](N)C(O)=O)N=C12 AYEKKSTZQYEZPU-RYUDHWBXSA-N 0.000 description 3
- 239000008363 phosphate buffer Substances 0.000 description 3
- 102000005962 receptors Human genes 0.000 description 3
- 108020003175 receptors Proteins 0.000 description 3
- 230000035882 stress Effects 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- 230000002792 vascular Effects 0.000 description 3
- UENLDOJJKXLRJI-ZETCQYMHSA-N (2s)-6-amino-2-(2-carboxyethylamino)hexanoic acid Chemical compound NCCCC[C@@H](C(O)=O)NCCC(O)=O UENLDOJJKXLRJI-ZETCQYMHSA-N 0.000 description 2
- VTYFITADLSVOAS-NSHDSACASA-N 1-(L-norleucin-6-yl)pyrraline Chemical compound OC(=O)[C@@H](N)CCCCN1C(CO)=CC=C1C=O VTYFITADLSVOAS-NSHDSACASA-N 0.000 description 2
- ILPUOPPYSQEBNJ-UHFFFAOYSA-N 2-methyl-2-phenoxypropanoic acid Chemical class OC(=O)C(C)(C)OC1=CC=CC=C1 ILPUOPPYSQEBNJ-UHFFFAOYSA-N 0.000 description 2
- 239000004475 Arginine Substances 0.000 description 2
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 2
- 230000010791 Copper Chelating Activity Effects 0.000 description 2
- 102000014824 Crystallins Human genes 0.000 description 2
- 108010064003 Crystallins Proteins 0.000 description 2
- 238000002965 ELISA Methods 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 241000282412 Homo Species 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 2
- 241000283973 Oryctolagus cuniculus Species 0.000 description 2
- 102000003923 Protein Kinase C Human genes 0.000 description 2
- 108090000315 Protein Kinase C Proteins 0.000 description 2
- 101710172711 Structural protein Proteins 0.000 description 2
- 238000010171 animal model Methods 0.000 description 2
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 2
- 229940090047 auto-injector Drugs 0.000 description 2
- QQFYLZXBFWWJHR-UHFFFAOYSA-M benzyl(triethyl)phosphanium;bromide Chemical compound [Br-].CC[P+](CC)(CC)CC1=CC=CC=C1 QQFYLZXBFWWJHR-UHFFFAOYSA-M 0.000 description 2
- 235000014633 carbohydrates Nutrition 0.000 description 2
- 150000001728 carbonyl compounds Chemical class 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 238000009833 condensation Methods 0.000 description 2
- 230000005494 condensation Effects 0.000 description 2
- 229910052802 copper Inorganic materials 0.000 description 2
- 239000010949 copper Substances 0.000 description 2
- 230000007423 decrease Effects 0.000 description 2
- 230000006735 deficit Effects 0.000 description 2
- 230000018044 dehydration Effects 0.000 description 2
- 238000006297 dehydration reaction Methods 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 238000000502 dialysis Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 208000028208 end stage renal disease Diseases 0.000 description 2
- 230000005284 excitation Effects 0.000 description 2
- 125000000623 heterocyclic group Chemical group 0.000 description 2
- 238000011835 investigation Methods 0.000 description 2
- 230000003902 lesion Effects 0.000 description 2
- 239000003446 ligand Substances 0.000 description 2
- 230000007774 longterm Effects 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- XZWYZXLIPXDOLR-UHFFFAOYSA-N metformin Chemical compound CN(C)C(=N)NC(N)=N XZWYZXLIPXDOLR-UHFFFAOYSA-N 0.000 description 2
- 229960003105 metformin Drugs 0.000 description 2
- FIGKGJVUYAFLBI-VIFPVBQESA-N methyl (2s)-2-[(2-acetamidoacetyl)amino]-6-aminohexanoate Chemical compound NCCCC[C@@H](C(=O)OC)NC(=O)CNC(C)=O FIGKGJVUYAFLBI-VIFPVBQESA-N 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 235000020777 polyunsaturated fatty acids Nutrition 0.000 description 2
- 239000013641 positive control Substances 0.000 description 2
- 230000036515 potency Effects 0.000 description 2
- 238000002731 protein assay Methods 0.000 description 2
- NHZMQXZHNVQTQA-UHFFFAOYSA-N pyridoxamine Chemical compound CC1=NC=C(CO)C(CN)=C1O NHZMQXZHNVQTQA-UHFFFAOYSA-N 0.000 description 2
- 230000002441 reversible effect Effects 0.000 description 2
- 210000002966 serum Anatomy 0.000 description 2
- 239000012064 sodium phosphate buffer Substances 0.000 description 2
- 238000010183 spectrum analysis Methods 0.000 description 2
- 239000011550 stock solution Substances 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- BOOXYSZJUWVNRE-JEDNCBNOSA-N (2s)-2,6-diaminohexanoic acid;2-oxopropanal Chemical class CC(=O)C=O.NCCCC[C@H](N)C(O)=O BOOXYSZJUWVNRE-JEDNCBNOSA-N 0.000 description 1
- JVTAAEKCZFNVCJ-UWTATZPHSA-M (R)-lactate Chemical compound C[C@@H](O)C([O-])=O JVTAAEKCZFNVCJ-UWTATZPHSA-M 0.000 description 1
- INGWEZCOABYORO-UHFFFAOYSA-N 2-(furan-2-yl)-7-methyl-1h-1,8-naphthyridin-4-one Chemical class N=1C2=NC(C)=CC=C2C(O)=CC=1C1=CC=CO1 INGWEZCOABYORO-UHFFFAOYSA-N 0.000 description 1
- SXERGJJQSKIUIC-UHFFFAOYSA-N 2-Phenoxypropionic acid Chemical class OC(=O)C(C)OC1=CC=CC=C1 SXERGJJQSKIUIC-UHFFFAOYSA-N 0.000 description 1
- WYMDDFRYORANCC-UHFFFAOYSA-N 2-[[3-[bis(carboxymethyl)amino]-2-hydroxypropyl]-(carboxymethyl)amino]acetic acid Chemical compound OC(=O)CN(CC(O)=O)CC(O)CN(CC(O)=O)CC(O)=O WYMDDFRYORANCC-UHFFFAOYSA-N 0.000 description 1
- STRVVRPNBAHXRJ-UHFFFAOYSA-N 2-hydroxynon-2-enal Chemical compound CCCCCCC=C(O)C=O STRVVRPNBAHXRJ-UHFFFAOYSA-N 0.000 description 1
- ZGCHLOWZNKRZSN-NTSWFWBYSA-N 3-deoxyglucosone Chemical compound OC[C@@H](O)[C@@H](O)CC(=O)C=O ZGCHLOWZNKRZSN-NTSWFWBYSA-N 0.000 description 1
- UHPMJDGOAZMIID-UHFFFAOYSA-N 3-deoxyglucosone Natural products OCC1OC(O)C(=O)CC1O UHPMJDGOAZMIID-UHFFFAOYSA-N 0.000 description 1
- 102000007469 Actins Human genes 0.000 description 1
- 108010085238 Actins Proteins 0.000 description 1
- 102000009027 Albumins Human genes 0.000 description 1
- 108010088751 Albumins Proteins 0.000 description 1
- 206010001580 Albuminuria Diseases 0.000 description 1
- 102000016912 Aldehyde Reductase Human genes 0.000 description 1
- 108010053754 Aldehyde reductase Proteins 0.000 description 1
- 244000144725 Amygdalus communis Species 0.000 description 1
- 102000006410 Apoproteins Human genes 0.000 description 1
- 108010083590 Apoproteins Proteins 0.000 description 1
- YZXBAPSDXZZRGB-DOFZRALJSA-M Arachidonate Chemical compound CCCCC\C=C/C\C=C/C\C=C/C\C=C/CCCC([O-])=O YZXBAPSDXZZRGB-DOFZRALJSA-M 0.000 description 1
- JQFZHHSQMKZLRU-IUCAKERBSA-N Arg-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@@H](N)CCCN=C(N)N JQFZHHSQMKZLRU-IUCAKERBSA-N 0.000 description 1
- 241000228212 Aspergillus Species 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- 102000004506 Blood Proteins Human genes 0.000 description 1
- 108010017384 Blood Proteins Proteins 0.000 description 1
- 0 CC(C)(C(O)=O)Oc(cc1)ccc1N(Cc(cc1)cc*1Cl)C(NC1=CC(Cl)=CCl=C1)=O Chemical compound CC(C)(C(O)=O)Oc(cc1)ccc1N(Cc(cc1)cc*1Cl)C(NC1=CC(Cl)=CCl=C1)=O 0.000 description 1
- KDXKERNSBIXSRK-RXMQYKEDSA-N D-lysine Chemical compound NCCCC[C@@H](N)C(O)=O KDXKERNSBIXSRK-RXMQYKEDSA-N 0.000 description 1
- 241001269524 Dura Species 0.000 description 1
- 102000016359 Fibronectins Human genes 0.000 description 1
- 108010067306 Fibronectins Proteins 0.000 description 1
- 229930091371 Fructose Natural products 0.000 description 1
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 description 1
- 239000005715 Fructose Substances 0.000 description 1
- 102000017011 Glycated Hemoglobin A Human genes 0.000 description 1
- 108060003393 Granulin Proteins 0.000 description 1
- 102000015779 HDL Lipoproteins Human genes 0.000 description 1
- 108010010234 HDL Lipoproteins Proteins 0.000 description 1
- 101000610640 Homo sapiens U4/U6 small nuclear ribonucleoprotein Prp3 Proteins 0.000 description 1
- 206010020880 Hypertrophy Diseases 0.000 description 1
- 108060003951 Immunoglobulin Proteins 0.000 description 1
- 102000001706 Immunoglobulin Fab Fragments Human genes 0.000 description 1
- 108010054477 Immunoglobulin Fab Fragments Proteins 0.000 description 1
- 238000012404 In vitro experiment Methods 0.000 description 1
- 102000007547 Laminin Human genes 0.000 description 1
- 108010085895 Laminin Proteins 0.000 description 1
- 102000004895 Lipoproteins Human genes 0.000 description 1
- 108090001030 Lipoproteins Proteins 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 102000006386 Myelin Proteins Human genes 0.000 description 1
- 108010083674 Myelin Proteins Proteins 0.000 description 1
- UBQYURCVBFRUQT-UHFFFAOYSA-N N-benzoyl-Ferrioxamine B Chemical compound CC(=O)N(O)CCCCCNC(=O)CCC(=O)N(O)CCCCCNC(=O)CCC(=O)N(O)CCCCCN UBQYURCVBFRUQT-UHFFFAOYSA-N 0.000 description 1
- QUYZZTTYATWSRY-UHFFFAOYSA-N N1C=CC=C2N=CC=C12 Chemical compound N1C=CC=C2N=CC=C12 QUYZZTTYATWSRY-UHFFFAOYSA-N 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- NUXSIDPKKIEIMI-UHFFFAOYSA-N Nepsilon-carboxymethyl-L-lysine Natural products OC(=O)C(N)CCCCNCC(O)=O NUXSIDPKKIEIMI-UHFFFAOYSA-N 0.000 description 1
- 208000028389 Nerve injury Diseases 0.000 description 1
- 241000208125 Nicotiana Species 0.000 description 1
- 235000002637 Nicotiana tabacum Nutrition 0.000 description 1
- 102000007079 Peptide Fragments Human genes 0.000 description 1
- 108010033276 Peptide Fragments Proteins 0.000 description 1
- 239000004793 Polystyrene Substances 0.000 description 1
- 102000001708 Protein Isoforms Human genes 0.000 description 1
- 108010029485 Protein Isoforms Proteins 0.000 description 1
- 102000005622 Receptor for Advanced Glycation End Products Human genes 0.000 description 1
- 108010045108 Receptor for Advanced Glycation End Products Proteins 0.000 description 1
- 208000017442 Retinal disease Diseases 0.000 description 1
- 206010038923 Retinopathy Diseases 0.000 description 1
- 101001110823 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) 60S ribosomal protein L6-A Proteins 0.000 description 1
- 101000712176 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) 60S ribosomal protein L6-B Proteins 0.000 description 1
- 239000002262 Schiff base Substances 0.000 description 1
- 150000004753 Schiff bases Chemical class 0.000 description 1
- 208000034189 Sclerosis Diseases 0.000 description 1
- 229940124639 Selective inhibitor Drugs 0.000 description 1
- 102000004243 Tubulin Human genes 0.000 description 1
- 108090000704 Tubulin Proteins 0.000 description 1
- 102100040374 U4/U6 small nuclear ribonucleoprotein Prp3 Human genes 0.000 description 1
- 238000002441 X-ray diffraction Methods 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 150000001323 aldoses Chemical group 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 108010078123 amadoriase Proteins 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 210000000709 aorta Anatomy 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 229940114078 arachidonate Drugs 0.000 description 1
- 108010062796 arginyllysine Proteins 0.000 description 1
- 210000001367 artery Anatomy 0.000 description 1
- 230000003140 astrocytic effect Effects 0.000 description 1
- 230000036523 atherogenesis Effects 0.000 description 1
- 210000002469 basement membrane Anatomy 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 150000001558 benzoic acid derivatives Chemical class 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 210000001124 body fluid Anatomy 0.000 description 1
- 239000010839 body fluid Substances 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 239000001058 brown pigment Substances 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 125000001951 carbamoylamino group Chemical group C(N)(=O)N* 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 230000003915 cell function Effects 0.000 description 1
- 230000002032 cellular defenses Effects 0.000 description 1
- 230000008614 cellular interaction Effects 0.000 description 1
- 230000036755 cellular response Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000002738 chelating agent Substances 0.000 description 1
- 125000003636 chemical group Chemical group 0.000 description 1
- 235000019504 cigarettes Nutrition 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 230000002596 correlated effect Effects 0.000 description 1
- 230000000875 corresponding effect Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 229960000958 deferoxamine Drugs 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 230000006325 deglycation Effects 0.000 description 1
- 230000008021 deposition Effects 0.000 description 1
- 238000001784 detoxification Methods 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 230000029087 digestion Effects 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- QLBHNVFOQLIYTH-UHFFFAOYSA-L dipotassium;2-[2-[bis(carboxymethyl)amino]ethyl-(carboxylatomethyl)amino]acetate Chemical compound [K+].[K+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O QLBHNVFOQLIYTH-UHFFFAOYSA-L 0.000 description 1
- 230000009266 disease activity Effects 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 238000002651 drug therapy Methods 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 210000002889 endothelial cell Anatomy 0.000 description 1
- 230000003511 endothelial effect Effects 0.000 description 1
- 239000002158 endotoxin Substances 0.000 description 1
- 150000002085 enols Chemical class 0.000 description 1
- 230000007071 enzymatic hydrolysis Effects 0.000 description 1
- 238000006047 enzymatic hydrolysis reaction Methods 0.000 description 1
- 210000003743 erythrocyte Anatomy 0.000 description 1
- 210000001508 eye Anatomy 0.000 description 1
- 208000019995 familial amyotrophic lateral sclerosis Diseases 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- 230000014509 gene expression Effects 0.000 description 1
- 230000001434 glomerular Effects 0.000 description 1
- 229960003681 gluconolactone Drugs 0.000 description 1
- 150000002303 glucose derivatives Chemical class 0.000 description 1
- 108091005995 glycated hemoglobin Proteins 0.000 description 1
- 230000013595 glycosylation Effects 0.000 description 1
- 238000006206 glycosylation reaction Methods 0.000 description 1
- 239000003102 growth factor Substances 0.000 description 1
- 238000001631 haemodialysis Methods 0.000 description 1
- 230000000322 hemodialysis Effects 0.000 description 1
- 210000003494 hepatocyte Anatomy 0.000 description 1
- 210000004276 hyalin Anatomy 0.000 description 1
- 150000002429 hydrazines Chemical class 0.000 description 1
- 230000000984 immunochemical effect Effects 0.000 description 1
- 102000018358 immunoglobulin Human genes 0.000 description 1
- 230000002055 immunohistochemical effect Effects 0.000 description 1
- 238000000099 in vitro assay Methods 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 238000004255 ion exchange chromatography Methods 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 208000017169 kidney disease Diseases 0.000 description 1
- 230000003907 kidney function Effects 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 230000003859 lipid peroxidation Effects 0.000 description 1
- 125000003588 lysine group Chemical group [H]N([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 1
- 229920002521 macromolecule Polymers 0.000 description 1
- 210000002540 macrophage Anatomy 0.000 description 1
- 108091005485 macrophage scavenger receptors Proteins 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 210000004379 membrane Anatomy 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 210000003584 mesangial cell Anatomy 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 210000001616 monocyte Anatomy 0.000 description 1
- 210000005012 myelin Anatomy 0.000 description 1
- 230000037125 natural defense Effects 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 230000008764 nerve damage Effects 0.000 description 1
- 201000001119 neuropathy Diseases 0.000 description 1
- 230000007823 neuropathy Effects 0.000 description 1
- ODUCDPQEXGNKDN-UHFFFAOYSA-N nitroxyl Chemical class O=N ODUCDPQEXGNKDN-UHFFFAOYSA-N 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- 230000003950 pathogenic mechanism Effects 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 210000000578 peripheral nerve Anatomy 0.000 description 1
- 208000033808 peripheral neuropathy Diseases 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 230000007505 plaque formation Effects 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- 229920002223 polystyrene Polymers 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 230000007425 progressive decline Effects 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 230000006916 protein interaction Effects 0.000 description 1
- 230000009145 protein modification Effects 0.000 description 1
- JUJWROOIHBZHMG-UHFFFAOYSA-O pyridinium Chemical compound C1=CC=[NH+]C=C1 JUJWROOIHBZHMG-UHFFFAOYSA-O 0.000 description 1
- 235000008151 pyridoxamine Nutrition 0.000 description 1
- 239000011699 pyridoxamine Substances 0.000 description 1
- 239000012048 reactive intermediate Substances 0.000 description 1
- 230000008707 rearrangement Effects 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 238000004007 reversed phase HPLC Methods 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 102000014452 scavenger receptors Human genes 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 230000000391 smoking effect Effects 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 229960002363 thiamine pyrophosphate Drugs 0.000 description 1
- 235000008170 thiamine pyrophosphate Nutrition 0.000 description 1
- 239000011678 thiamine pyrophosphate Substances 0.000 description 1
- YXVCLPJQTZXJLH-UHFFFAOYSA-N thiamine(1+) diphosphate chloride Chemical compound [Cl-].CC1=C(CCOP(O)(=O)OP(O)(O)=O)SC=[N+]1CC1=CN=C(C)N=C1N YXVCLPJQTZXJLH-UHFFFAOYSA-N 0.000 description 1
- 230000007838 tissue remodeling Effects 0.000 description 1
- 230000007306 turnover Effects 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- 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
- A23L3/00—Preservation of foods or foodstuffs, in general, e.g. pasteurising, sterilising, specially adapted for foods or foodstuffs
- A23L3/34—Preservation of foods or foodstuffs, in general, e.g. pasteurising, sterilising, specially adapted for foods or foodstuffs by treatment with chemicals
- A23L3/3454—Preservation of foods or foodstuffs, in general, e.g. pasteurising, sterilising, specially adapted for foods or foodstuffs by treatment with chemicals in the form of liquids or solids
- A23L3/3463—Organic compounds; Microorganisms; Enzymes
- A23L3/3526—Organic compounds containing nitrogen
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
- A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/17—Amides, e.g. hydroxamic acids having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/196—Carboxylic acids, e.g. valproic acid having an amino group the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
- A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/60—Salicylic acid; Derivatives thereof
- A61K31/606—Salicylic acid; Derivatives thereof having amino groups
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/10—Antimycotics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P39/00—General protective or antinoxious agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
Definitions
- Patent No. 6,605,642 filed March 08, 2001, which is a continuation-in-part ofapplication Serial No. 09/543,703, filed April 05, 2000, now U.S. Patent 6,337,350, which is related to provisional application Serial No. 60/127,835, filed 05 April 1999, which are all incorporated herein by reference.
- the present invention relates generally to the modification and aging of proteins through reaction with glucose and other reducing sugars, such as fructose or ribose and more particularly to the inhibition of nonenzymatic glycation of proteins which often results in formation of advanced glycation endproducts and crosslinks.
- Nonenzymatic glycation is a complex series of reactions between reducing sugars and amino groups of proteins, lipids, and
- Amadori product further undergo a series of reactions through dicarbonyl intermediates to form AGEs.
- the significance of a similar process in biology became evident only after the discovery of the glycosylated hemoglobins and their increased presence in diabetic patients (Rahbar, 1968; Rahbar et al., 1969).
- these nonenzymatic reactions are accelerated and cause increased AGE formation and increased glycation of long-lived proteins such as collagen, fibronectin, tubulin, lens crystallin, myelin, laminin and actin, in addition to hemoglobin and albumin, and also of LDL associated lipids and apoprotein.
- brown pigments with spectral and fluorescent properties similar to those of late-stage Maillard products have also been found in vivo in association with several long- lived proteins such as lens crystallin proteins and collagen from aged individuals.
- An age-related linear increase in pigments was observed in human dura collagen between the ages of 20 to 90 years.
- AGE modified proteins increase slowly with aging and are thought to contribute to normal tissue remodeling. Their level increases markedly in diabetic patients as a result of sustained high blood sugar levels and lead to tissue damage through a variety of mechanisms including alteration of tissue protein structure and function, stimulation of cellular responses through AGE specific receptors or the generation of reactive oxygen species (ROS) (for a recent review see Boel et al., 1995).
- ROS reactive oxygen species
- AGEs advanced glycation end products
- tissue damage to the kidney by AGEs leads to progressive decline inrenal function, end-stage renal disease (ESRD) (Makita et al, 1994), and accumulation of low-molecular-weight (LMW) AGE peptides (glycotoxins) (Koschinsky et al., 1997) in the serum of patients with ESRD (Makita et al., 1991).
- LMW low-molecular-weight
- LDL low density lipoprotein
- collagen Miyata et al., 1993
- Hb hemoglobin
- DCCT Diabetic Control and Complications Trial
- MG Methylglyoxal
- RAGE a member of the immunoglobulin superfamily
- MG binds to and irreversibly modifies arginine and lysine residues in proteins.
- MG modified proteins have been shown to be ligands for the AGE receptor
- Lipid peroxidation of polyunsaturated fatty acids also yields carbonyl compounds; some are identical to those formed from carbohydrates (Al-Abed et al., 1996), such as MG and GO, and others are characteristic of lipids, such as malondialdehyde (MDA) and 4-hydroxynonenal (HNE) (Requena et al., 1997).
- MDA malondialdehyde
- HNE 4-hydroxynonenal
- the latter two carbonyl compounds produce lipoxidation products (Al-Abed et al., 1996; Requena et al., 1997).
- crosslinking structures characterized to date, on the basis of chemical and spectroscopic analyses, constitute only a small fraction of the AGE crosslinks which occur in vivo, with the major crosslinking structure(s) still unknown.
- CMA N-omega-carboxymethylarginine
- IgM anti-IgG-AGE appears to be associated with clinical measurements of rheumatoid arthritis activity (Lucey et al., 2000).
- a correlation between AGEs and rheumatoid arthritis was also made in North American Indians (Newkirket al., 1998).
- AGEs are present in brain plaques in Alzheimer's disease and the presence of AGEs may help promote the development of Alzheimer's disease (Durany et al., 1999; Munch et al., 1998; Munch et al., 1997).
- Examples are pyrraline, pentosidine, carboxymethyl-lysine (CML), carboxyethyl-lysine (CEL), crossline, pyrrolopyridinium, methylglyoxal lysine dimer (MOLD), Arg-Lys imidazole, arginine pyridinium, cypentodine, piperidinedinone enol and alkyl, formyl, diglycosyl-pyrrole (Vlassara, 1994).
- Examples are D-lysine (Sensi et al., 1993), desferrioxamine (Takagi et al., 1995), D-penicillamme (McPherson et al., 1988), thiamine pyrophosphate and pyridoxamine (Booth et al., 1997) which have no structural similarities to aminoguanidine.
- the compounds of the present invention can be used to inhibit this process of nonenzymatic glycation and crosslinking and therefore to inhibit some of the ill effects caused by diabetes or by aging.
- the compounds are also useful for preventing premature aging, rheumatoid arthritis, Alzheimer's disease, uremia, neurotoxicity, atherosclerosis, and spoilage of proteins in food and can prevent discoloration of teeth.
- Figures 1 and2 showthe results for compounds LR103-115 in the post- Amadori protein assay.
- Figure 1 shows the inhibition of post-Amadori AGE formation by LR103-108 at concentrations of 0.05, 0.10, 0.50, 1.00 and 5.00 mM.
- Figure 2 shows the inhibition of post-
- FIGS. 3 and 4 show examples of copper-chelating activity of some of the novel compounds including LR103, LR104, LR105 and LR106.
- the IC 50 of LRl 03 is ⁇ 75 ⁇ M and that of LRl 04 ⁇ lOO ⁇ M, demonstrating these compounds to be strong chelators of copper.
- Figures 5 and 6 demonstrate dicarbonyl scavenging properties for compounds LRl 03-
- Figure 5 shows data from MGO trapping and Figure 6 shows data from glycolaldehyde trapping activities of the compounds. These classes of compounds have both transient-metal- chelating and dicarbonyl scavenging properties.
- Figure 7 shows the structure of compound LRl 03.
- Figure 8 shows the structure of compound LRl 04.
- Figure 9 shows the structure of compound LRl 05.
- Figure 10 shows the structure of compound LRl 06
- Figure 11 shows the structure of compound LRl 07
- Figure 12 shows the structure of compound LR108
- Figure 13 shows the structure of compound LRl 09 [00032]
- Figure 14 shows the structure of compound LRl 10 [00033]
- Figure 15 shows the structure of compound LRl 11 [00034]
- Figure 16 shows the structure of compound LRl 12 [00035]
- Figure 17 shows the structure of compound LRl 13
- Figure 18 shows the structure of compound LRl 14
- Figure 19 shows the structure of compound LRl 15
- Glu assay a specific assay for the early stage of glycation (type A or B inhibitor). Most of these compounds strongly inhibit the post-Amadori glycation as demonstrated by the B S A-glucose and G.K.-Ribose assays (type D inliibitors), and a good number of them are powerful inhibitors of AGE protein crosslinking, as evidenced by a specific ELIS A assay (type E inhibitors as described by Baynes Classification (Khalifah et al., 1999).
- guanidino compound inhibitors such as two known inhibitors of glycation (aminoguanidine and metformin) is that they are postulated to trap MG and other -.-dicarbonyl intermediates of glycation.
- a most recent study has documented the reaction of metformin with MG and glyoxal (GO), forming guanidino- dicarbonyl adducts further supporting this idea (Ruggiero-Lopez et al., 1999).
- the compounds and their useful compositions utilized in the present invention contain agents capable of reacting with the highly active carbonyl intermediate of an early glycation product thereby preventing those early products from later forming the advanced glycation endproducts which lead to protein crosslinking and to protein aging.
- LR103-LR115 Compounds of the present invention are shown in Figures 7-19 as LR103-LR115, and were screened for inhibitory effects on protein glycation and AGE-formation.
- the names assigned to these structures are: LRl 03: l-[(4-chlorobenzyl)-3-(3,4-dichlorophenylureido)]-4-phenoxyisobutyric acid.
- LR104 4-(4-fluoro-3-chlorophenylurido) phenoxyisobutyrylamidophenyl-2-carboxylic acid.
- LRl 05 l[(2-fluoro-6-chlorobenzyl)-3-(3,4-dichlorophenyureido)]-4-phenoxyisobutyric acid.
- LRl 06 4-(4-chlorobenzylaminophenoxyisobutyric) acid.
- LRl 07 2-chlorobenzene- 1 ,4-bis(4-ureidophenoxyisobutyric acid) .
- LRl 08 l-[(4-chlorobenzyl)-3-(3,5-dichlorophenyureido)]-4-phenoxyisobutyric acid.
- LRl 09 l -[(2-fluoro-6-chlorobenzyl)-3-(2-fluoro-6-chlorophenylureido)]-4- phenoxyisobutyric acid.
- LRl 10 4-(l,2,3,4-tetrahydroacridine-9-carboxamidophenoxyisobutyric)acid.
- LRl 11 8-quinolinoxy acetic acid
- LRl 12 4,4'-bis [(methyleneoxyethyleneamino) phenoxy] isobutyric acid.
- LRl 13 L- 8 -quinolinolyl (acetylhistidine)
- LRl 14 4-[(3,5-dichlorophenyureido) phenoxyisobutyrylamido]-2-hydroxybenzene-4- carboxylic acid.
- LRl 15 L, ⁇ -4-[(3,5-dichlorophenyureido) phenoxyisobutyrylamido] phenylalanine.
- the above compounds are capable of inhibiting the formation of advanced glycation end products on target proteins and the resulting protein crosslinking.
- thirteen new compounds which are derivatives of previously reported inhibitors of glycation and AGE formation, were investigated and also found to be inhibitors of multistage glycation, AGE formation and AGE-protein-cross-linking.
- An ideal agent would prevent the formation of the chromophore and its associated crosslinks of proteins and trapping of proteins on the other proteins, such as occurs in arteries and in the kidneys.
- the compounds of the invention may be administered to mammals including humans to prevent or reduce protein glycation and crosslinking (protein aging).
- the compounds may be administered orally at variable dosage depending on the activity of each agent in a single or individual amounts. In addition the compounds may be administered parenterally or rectally.
- the compounds of the invention, the rationale behind the different assay methods of the present invention, and their use are illustrated by the following Examples.
- Example 1 Hemoglobin- ⁇ -Gluconolactone f ⁇ -Glu) Assay [00047]
- the ⁇ -Glu assay is a specific method for investigation of inhibitors of the early stage of glycation.
- Hb Alc hemoglobin
- Hb Alc glycated Hb
- A Hb Alc concentration in the baseline control tube not treated with ⁇ -Glu
- B is the HbA lc concentration in blood incubated with ⁇ -Glu
- C is the HbA lc content of the test tube treated both with ⁇ -Glu and the inhibitor compound.
- Example 3 N-Acetyl-Glycyl-Lysine Methyl Ester (G.K. Peptide - Ribose Assay [00052] Evaluation of the late glycation products (AGEs), and AGE-inhibition by the new inhibitor compounds was tested by incubation of G.K. peptide in ribose in the presence or the absence of the agent, followed by determination of chromophores generated in the course of glycation and AGE formation through determination of their specific fluorescence.
- GK peptide (Sigma) 80 mg/mL in 0.5 M sodium phosphate buffer pH 7.4
- Table 3 shows the inhibitory effects of the compounds to block specific fluorescence of protein- AGE in these separate determinations, using G.K. peptide-ribose assay. The results of this assay show that most of the thirteen compounds investigated have strong inhibitory effects. Table 3 Percent Inhibition by LR103-LR115 in the G.K. -Ribose Assay
- AGE- free, Amardori rich proteins using BSA as protein and ribose as glycating agents was prepared according to Khalifa et al., followed by extensive dialysis at 4°C for 24 hours against phosphate buffer. Dialysed preparation was then diluted, warmed and incubated for 7 days at 37°C in the presence and the absence of candidate inhibitor.
- ELISA detection of AGE products was performed as described by Khalifa et al., except that 0.5-1 (instead of 0.3) ⁇ g of protein was coated into each polystyrene well, and Superblot buffer was used for blocking the wells.
- a rabbit polyclonal anti-R ase-AGE was prepared using an established protocol (Makita et al., 1992) and used at 1:1000 dilution. The results using compounds LR103-
- LR115 are shown in Figures 1 and 2.
- This assay was performed according to Price et al. (2001). The kinetics of oxidation of ascorbic acid (AA) at the rate of decrease in absorbance at 265 nm was measured. For studies with AGE inhibitors, the ascorbic acid was added to initiate the reaction. Aliquots were removed at 0, 15, 30, 45, and 60 minutes and transferred to autoinjector vials containing
- Figures 5 and 6 demonstrate dicarbonyl scavenging properties of all the compounds.
- Figure 5 shows data from methylglyoxal (MGO) trapping.
- Figure 6 shows data for all the compounds from glycolaldehyde trapping. The data indicate that these classes of compounds have both transient-metal-chelating and dicarbonyl scavenging properties.
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Pain & Pain Management (AREA)
- Neurosurgery (AREA)
- Neurology (AREA)
- Diabetes (AREA)
- Nutrition Science (AREA)
- Rheumatology (AREA)
- Polymers & Plastics (AREA)
- Food Science & Technology (AREA)
- Microbiology (AREA)
- Urology & Nephrology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Obesity (AREA)
- Cardiology (AREA)
- Hospice & Palliative Care (AREA)
- Psychiatry (AREA)
- Vascular Medicine (AREA)
- Emergency Medicine (AREA)
- Oncology (AREA)
- Immunology (AREA)
- Endocrinology (AREA)
- Physical Education & Sports Medicine (AREA)
- Communicable Diseases (AREA)
- Toxicology (AREA)
Abstract
Description
Claims
Priority Applications (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU2004211899A AU2004211899C1 (en) | 2003-02-05 | 2004-02-05 | Novel inhibitors of formation of advanced glycation endproducts (AGEs) |
CA2514356A CA2514356C (en) | 2003-02-05 | 2004-02-05 | Novel inhibitors of formation of advanced glycation endproducts (ages) |
EP04708575A EP1594492B1 (en) | 2003-02-05 | 2004-02-05 | Novel inhibitors of formation of advanced glycation endproducts (ages) |
DE602004017962T DE602004017962D1 (en) | 2003-02-05 | 2004-02-05 | NEW HEMMER OF THE EDUCATION OF AGES (ADVANCED GLYCATION ENDPRODUCTS) |
JP2006503321A JP2007525418A (en) | 2003-02-05 | 2004-02-05 | Novel inhibitors of advanced glycation end product (AGE) formation |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US10/358,403 US7030133B2 (en) | 1999-04-05 | 2003-02-05 | Inhibitors of formation of advanced glycation endproducts (AGEs) |
US10/358,403 | 2003-02-05 |
Publications (3)
Publication Number | Publication Date |
---|---|
WO2004071416A2 true WO2004071416A2 (en) | 2004-08-26 |
WO2004071416A3 WO2004071416A3 (en) | 2004-10-14 |
WO2004071416B1 WO2004071416B1 (en) | 2004-11-25 |
Family
ID=32867908
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US2004/003203 WO2004071416A2 (en) | 2003-02-05 | 2004-02-05 | Novel inhibitors of formation of advanced glycation endproducts (ages) |
Country Status (8)
Country | Link |
---|---|
US (1) | US7030133B2 (en) |
EP (1) | EP1594492B1 (en) |
JP (1) | JP2007525418A (en) |
AT (1) | ATE415159T1 (en) |
AU (1) | AU2004211899C1 (en) |
CA (1) | CA2514356C (en) |
DE (1) | DE602004017962D1 (en) |
WO (1) | WO2004071416A2 (en) |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2005040102A2 (en) * | 2003-10-28 | 2005-05-06 | Dr. Reddy's Laboratories Ltd. | Novel compounds and their use as antidiabetic and hypolipidemic agents, process for their preparation and pharmaceutical compositions containing them |
US7030133B2 (en) | 1999-04-05 | 2006-04-18 | City Of Hope | Inhibitors of formation of advanced glycation endproducts (AGEs) |
US7320988B2 (en) | 2003-10-27 | 2008-01-22 | City Of Hope | Methods of lowering lipid levels in a mammal |
DE102007041232A1 (en) | 2007-08-30 | 2009-03-05 | Henkel Ag & Co. Kgaa | Washing and cleaning composition for cleaning of textiles and hard surfaces and for removal of burned or persistent dirt, comprises urea derivatives, which is sulfonyl urea |
DE102007054653A1 (en) | 2007-11-14 | 2009-05-20 | Henkel Ag & Co. Kgaa | Use of thiourea derivative to degrade advanced glycation end-products, Maillard-products and Amadori products and to prepare medicament to inhibit skin diseases during diabetes and to treat e.g. cataract, arthritis and Alzheimer's disease |
Families Citing this family (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8053449B2 (en) * | 2005-10-05 | 2011-11-08 | Cell Viable Corporation | Method for inhibiting AGE complex formation |
US20120071502A1 (en) * | 2010-09-17 | 2012-03-22 | Cell Viable Corporation | Novel phenoxyisobutyric acid compounds and methods for synthesis |
US9808434B2 (en) | 2011-01-27 | 2017-11-07 | City Of Hope | Compound for treating cancer and diabetes |
WO2012103523A2 (en) | 2011-01-27 | 2012-08-02 | Samuel Rahbar | Novel modulators of development of adipocyte and cancer cells |
JP6306825B2 (en) * | 2012-11-30 | 2018-04-04 | 上野製薬株式会社 | Saccharification product formation inhibitor |
Family Cites Families (20)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE3573511D1 (en) * | 1984-03-15 | 1989-11-16 | Ciba Geigy Ag | Use of quinoline derivatives to protect cultivated plants |
US5272176A (en) | 1984-03-19 | 1993-12-21 | The Rockefeller University | Advanced glycation inhibitors containing amino-benzoic acids and derivatives, and methods of use |
US5100919A (en) | 1984-03-19 | 1992-03-31 | The Rockefeller University | Biguanides and derivatives thereof as inhibitors of advanced glycosylation of a target protein |
DE3410927A1 (en) | 1984-03-24 | 1985-10-03 | Hoechst Ag, 6230 Frankfurt | FULLY FLAVORED POLYESTER, METHOD FOR THE PRODUCTION THEREOF AND CORRESPONDING SHAPED BODY |
US5268500A (en) | 1987-06-15 | 1993-12-07 | Montefiore Medical Center | Compound, composition and method for the reduction of lipids the modification of the affinity of hemoblogin for oxygen and the prevention of platelet aggregation |
US5093367A (en) | 1988-06-15 | 1992-03-03 | Montefiore Medical Center | Method of synthesis and novel compounds for pharmaceutical uses |
US4921997A (en) | 1988-06-15 | 1990-05-01 | Montefiore Medical Center | Method of synthesis and novel compounds for pharmaceutical uses |
US5677330A (en) | 1990-02-12 | 1997-10-14 | The Center For Innovative Technology | Medical uses of allosteric hemoglobin modifier compounds in patient care |
US6046222A (en) | 1993-09-15 | 2000-04-04 | Warner-Lambert Company | Use of thiazolidinedione derivatives in the treatment of polycystic ovary syndrome, gestational diabetes and disease states at risk for progressing to noninsulin-dependent diabetes mellitus |
WO1995031192A1 (en) | 1994-05-16 | 1995-11-23 | Thomas Jefferson University | Method and use of agents to inhibit protein polymerization and methods of identifying these agents |
US5661139A (en) | 1995-01-13 | 1997-08-26 | Alteon Inc. | Bis-(2-aryl) hydrazones |
US5962651A (en) | 1995-01-27 | 1999-10-05 | Montefiore Medical Center | Modified hemoglobin and its use as a component of an artificial blood substitute |
US5602277A (en) | 1995-03-30 | 1997-02-11 | Biocryst Pharmaceuticals, Inc. | Substituted benzene derivatives useful as neuraminidase inhibitors |
US5716987A (en) | 1996-06-21 | 1998-02-10 | Bristol-Myers Squibb Company | Prophylactic and therapeutic treatment of skin sensitization and irritation |
US6605642B2 (en) | 1999-04-05 | 2003-08-12 | City Of Hope | Inhibitors of formation of advanced glycation endproducts (AGES) |
US7030133B2 (en) | 1999-04-05 | 2006-04-18 | City Of Hope | Inhibitors of formation of advanced glycation endproducts (AGEs) |
US6787566B2 (en) | 1999-04-05 | 2004-09-07 | City Of Hope | Breakers of advanced glycation endproducts |
US6589944B1 (en) | 1999-04-05 | 2003-07-08 | City Of Hope | Breakers of advanced glycation endproducts |
EP1165064B1 (en) * | 1999-04-05 | 2004-02-25 | City of Hope | Novel inhibitors of formation of advanced glycation endproducts (age's) |
AU776162B2 (en) | 1999-04-29 | 2004-08-26 | City Of Hope | Pentoxifylline, pioglitazone and metformin are inhibitors of formation of advanced glycation endproducts (AGE's) |
-
2003
- 2003-02-05 US US10/358,403 patent/US7030133B2/en not_active Expired - Lifetime
-
2004
- 2004-02-05 CA CA2514356A patent/CA2514356C/en not_active Expired - Lifetime
- 2004-02-05 DE DE602004017962T patent/DE602004017962D1/en not_active Expired - Lifetime
- 2004-02-05 JP JP2006503321A patent/JP2007525418A/en active Pending
- 2004-02-05 WO PCT/US2004/003203 patent/WO2004071416A2/en active Search and Examination
- 2004-02-05 AT AT04708575T patent/ATE415159T1/en not_active IP Right Cessation
- 2004-02-05 AU AU2004211899A patent/AU2004211899C1/en not_active Expired
- 2004-02-05 EP EP04708575A patent/EP1594492B1/en not_active Expired - Lifetime
Non-Patent Citations (1)
Title |
---|
See references of EP1594492A4 * |
Cited By (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7030133B2 (en) | 1999-04-05 | 2006-04-18 | City Of Hope | Inhibitors of formation of advanced glycation endproducts (AGEs) |
US7320988B2 (en) | 2003-10-27 | 2008-01-22 | City Of Hope | Methods of lowering lipid levels in a mammal |
US7652037B2 (en) | 2003-10-27 | 2010-01-26 | City Of Hope | Methods of lowering lipid levels in a mammal |
WO2005040102A2 (en) * | 2003-10-28 | 2005-05-06 | Dr. Reddy's Laboratories Ltd. | Novel compounds and their use as antidiabetic and hypolipidemic agents, process for their preparation and pharmaceutical compositions containing them |
WO2005040102A3 (en) * | 2003-10-28 | 2006-03-23 | Reddys Lab Ltd Dr | Novel compounds and their use as antidiabetic and hypolipidemic agents, process for their preparation and pharmaceutical compositions containing them |
DE102007041232A1 (en) | 2007-08-30 | 2009-03-05 | Henkel Ag & Co. Kgaa | Washing and cleaning composition for cleaning of textiles and hard surfaces and for removal of burned or persistent dirt, comprises urea derivatives, which is sulfonyl urea |
DE102007054653A1 (en) | 2007-11-14 | 2009-05-20 | Henkel Ag & Co. Kgaa | Use of thiourea derivative to degrade advanced glycation end-products, Maillard-products and Amadori products and to prepare medicament to inhibit skin diseases during diabetes and to treat e.g. cataract, arthritis and Alzheimer's disease |
Also Published As
Publication number | Publication date |
---|---|
AU2004211899A1 (en) | 2004-08-26 |
CA2514356C (en) | 2012-05-08 |
CA2514356A1 (en) | 2004-08-26 |
US20030220362A1 (en) | 2003-11-27 |
EP1594492A2 (en) | 2005-11-16 |
JP2007525418A (en) | 2007-09-06 |
WO2004071416B1 (en) | 2004-11-25 |
AU2004211899B2 (en) | 2009-09-24 |
EP1594492B1 (en) | 2008-11-26 |
DE602004017962D1 (en) | 2009-01-08 |
US7030133B2 (en) | 2006-04-18 |
AU2004211899C1 (en) | 2010-05-20 |
WO2004071416A3 (en) | 2004-10-14 |
ATE415159T1 (en) | 2008-12-15 |
EP1594492A4 (en) | 2007-04-18 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US6605642B2 (en) | Inhibitors of formation of advanced glycation endproducts (AGES) | |
EP1165064B1 (en) | Novel inhibitors of formation of advanced glycation endproducts (age's) | |
AU2002252184A1 (en) | Novel inhibitors of formation of advanced glycation endproducts (AGEs) | |
US6693106B2 (en) | Pentoxifylline, pioglitazone and metformin are inhibitors of formation of advanced glycation endproducts (AGE's) | |
Rahbar et al. | Evidence that pioglitazone, metformin and pentoxifylline are inhibitors of glycation | |
EP1372627B1 (en) | Use of breakers of advanced glycation endproducts for treating deleterious effects of aging and debilitating diseases | |
AU2001255195B2 (en) | Use of breakers of advanced glycation endproducts for treating deleterious effects of aging and debilitating diseases | |
CA2514356C (en) | Novel inhibitors of formation of advanced glycation endproducts (ages) | |
SG188563A1 (en) | Novel phenoxyisobutyric acid compounds and methods for synthesis |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AK | Designated states |
Kind code of ref document: A2 Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BW BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE EG ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NA NI NO NZ OM PG PH PL PT RO RU SC SD SE SG SK SL SY TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW |
|
AL | Designated countries for regional patents |
Kind code of ref document: A2 Designated state(s): BW GH GM KE LS MW MZ SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LU MC NL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG |
|
121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
B | Later publication of amended claims |
Effective date: 20041012 |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2514356 Country of ref document: CA |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2006503321 Country of ref document: JP |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2004211899 Country of ref document: AU |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2004708575 Country of ref document: EP |
|
ENP | Entry into the national phase |
Ref document number: 2004211899 Country of ref document: AU Date of ref document: 20040205 Kind code of ref document: A |
|
WWP | Wipo information: published in national office |
Ref document number: 2004211899 Country of ref document: AU |
|
WWP | Wipo information: published in national office |
Ref document number: 2004708575 Country of ref document: EP |
|
DPEN | Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed from 20040101) |