CA2599843C - Selective glycosidase inhibitors, methods of making inhibitors, and uses thereof - Google Patents
Selective glycosidase inhibitors, methods of making inhibitors, and uses thereof Download PDFInfo
- Publication number
- CA2599843C CA2599843C CA2599843A CA2599843A CA2599843C CA 2599843 C CA2599843 C CA 2599843C CA 2599843 A CA2599843 A CA 2599843A CA 2599843 A CA2599843 A CA 2599843A CA 2599843 C CA2599843 C CA 2599843C
- Authority
- CA
- Canada
- Prior art keywords
- thiazoline
- dideoxy
- glucopyranoso
- pyrano
- thiazole
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- 238000000034 method Methods 0.000 title abstract description 28
- 239000003316 glycosidase inhibitor Substances 0.000 title abstract description 6
- 239000003112 inhibitor Substances 0.000 title description 141
- 150000001875 compounds Chemical class 0.000 claims abstract description 127
- 229940002612 prodrug Drugs 0.000 claims abstract description 12
- 239000000651 prodrug Substances 0.000 claims abstract description 12
- 230000002401 inhibitory effect Effects 0.000 claims abstract description 9
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 9
- 229910052739 hydrogen Inorganic materials 0.000 claims description 117
- 230000005764 inhibitory process Effects 0.000 claims description 26
- 150000003839 salts Chemical class 0.000 claims description 26
- 208000024827 Alzheimer disease Diseases 0.000 claims description 20
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 20
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 19
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 19
- 239000000126 substance Substances 0.000 claims description 18
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 17
- 208000035475 disorder Diseases 0.000 claims description 11
- 239000003937 drug carrier Substances 0.000 claims description 8
- 229940124639 Selective inhibitor Drugs 0.000 claims description 7
- 206010028980 Neoplasm Diseases 0.000 claims description 6
- 208000034799 Tauopathies Diseases 0.000 claims description 6
- 201000011510 cancer Diseases 0.000 claims description 6
- OVRNDRQMDRJTHS-UHFFFAOYSA-N N-acelyl-D-glucosamine Natural products CC(=O)NC1C(O)OC(CO)C(O)C1O OVRNDRQMDRJTHS-UHFFFAOYSA-N 0.000 claims description 5
- MBLBDJOUHNCFQT-LXGUWJNJSA-N N-acetylglucosamine Natural products CC(=O)N[C@@H](C=O)[C@@H](O)[C@H](O)[C@H](O)CO MBLBDJOUHNCFQT-LXGUWJNJSA-N 0.000 claims description 5
- 206010012601 diabetes mellitus Diseases 0.000 claims description 5
- 238000002560 therapeutic procedure Methods 0.000 claims description 5
- 238000003776 cleavage reaction Methods 0.000 claims description 4
- 230000004770 neurodegeneration Effects 0.000 claims description 4
- 208000015122 neurodegenerative disease Diseases 0.000 claims description 4
- 230000007017 scission Effects 0.000 claims description 4
- 208000010125 myocardial infarction Diseases 0.000 claims description 3
- 229950006780 n-acetylglucosamine Drugs 0.000 claims description 3
- OVRNDRQMDRJTHS-FMDGEEDCSA-N N-acetyl-beta-D-glucosamine Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O OVRNDRQMDRJTHS-FMDGEEDCSA-N 0.000 claims description 2
- AREJBZPGVDSCFV-LMHBHQSJSA-N [(3ar,5r,6s,7r,7ar)-6,7-diacetyloxy-2-(2-methylpropyl)-5,6,7,7a-tetrahydro-3ah-pyrano[3,2-d][1,3]thiazol-5-yl]methyl acetate Chemical compound S1C(CC(C)C)=N[C@H]2[C@@H]1O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@@H]2OC(C)=O AREJBZPGVDSCFV-LMHBHQSJSA-N 0.000 claims 6
- QWLSGKMXAHXJDM-LMHBHQSJSA-N [(3ar,5r,6s,7r,7ar)-6,7-diacetyloxy-2-butyl-5,6,7,7a-tetrahydro-3ah-pyrano[3,2-d][1,3]thiazol-5-yl]methyl acetate Chemical compound S1C(CCCC)=N[C@H]2[C@@H]1O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@@H]2OC(C)=O QWLSGKMXAHXJDM-LMHBHQSJSA-N 0.000 claims 6
- PFPXOCGKVAYLDW-DIAXPKBXSA-N [(3ar,5r,6s,7r,7ar)-6,7-diacetyloxy-2-ethyl-5,6,7,7a-tetrahydro-3ah-pyrano[3,2-d][1,3]thiazol-5-yl]methyl acetate Chemical compound S1C(CC)=N[C@H]2[C@@H]1O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@@H]2OC(C)=O PFPXOCGKVAYLDW-DIAXPKBXSA-N 0.000 claims 6
- COARJWAHYFNYJD-JVNHZCFISA-N [(3ar,5r,6s,7r,7ar)-6,7-diacetyloxy-2-pentyl-5,6,7,7a-tetrahydro-3ah-pyrano[3,2-d][1,3]thiazol-5-yl]methyl acetate Chemical compound S1C(CCCCC)=N[C@H]2[C@@H]1O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@@H]2OC(C)=O COARJWAHYFNYJD-JVNHZCFISA-N 0.000 claims 6
- QZKZZLAADHHBPD-UTGUJQJDSA-N [(3ar,5r,6s,7r,7ar)-6,7-diacetyloxy-2-propan-2-yl-5,6,7,7a-tetrahydro-3ah-pyrano[3,2-d][1,3]thiazol-5-yl]methyl acetate Chemical compound S1C(C(C)C)=N[C@H]2[C@@H]1O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@@H]2OC(C)=O QZKZZLAADHHBPD-UTGUJQJDSA-N 0.000 claims 6
- VRJFQCRQLPVYQE-JPIRQXTESA-N [(3ar,5r,6s,7r,7ar)-6,7-diacetyloxy-2-propyl-5,6,7,7a-tetrahydro-3ah-pyrano[3,2-d][1,3]thiazol-5-yl]methyl acetate Chemical compound S1C(CCC)=N[C@H]2[C@@H]1O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@@H]2OC(C)=O VRJFQCRQLPVYQE-JPIRQXTESA-N 0.000 claims 6
- VUWIPARUGVLNEP-NENRSDFPSA-N (3ar,5r,6s,7r,7ar)-2-butyl-5-(hydroxymethyl)-5,6,7,7a-tetrahydro-3ah-pyrano[3,2-d][1,3]thiazole-6,7-diol Chemical compound S1C(CCCC)=N[C@H]2[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]2O VUWIPARUGVLNEP-NENRSDFPSA-N 0.000 claims 3
- ACNLJPLCGRIHJF-GPMKSPRZSA-N (3ar,5r,6s,7r,7ar)-2-ethyl-5-(hydroxymethyl)-5,6,7,7a-tetrahydro-3ah-pyrano[3,2-d][1,3]thiazole-6,7-diol Chemical compound S1C(CC)=N[C@H]2[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]2O ACNLJPLCGRIHJF-GPMKSPRZSA-N 0.000 claims 3
- SZIWBYUQAXWJOA-NENRSDFPSA-N (3ar,5r,6s,7r,7ar)-5-(hydroxymethyl)-2-(2-methylpropyl)-5,6,7,7a-tetrahydro-3ah-pyrano[3,2-d][1,3]thiazole-6,7-diol Chemical compound S1C(CC(C)C)=N[C@H]2[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]2O SZIWBYUQAXWJOA-NENRSDFPSA-N 0.000 claims 3
- IZRUBNLPKMQXIY-YNVCDSSISA-N (3ar,5r,6s,7r,7ar)-5-(hydroxymethyl)-2-pentyl-5,6,7,7a-tetrahydro-3ah-pyrano[3,2-d][1,3]thiazole-6,7-diol Chemical compound S1C(CCCCC)=N[C@H]2[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]2O IZRUBNLPKMQXIY-YNVCDSSISA-N 0.000 claims 3
- FOOVVGIBHSAEPH-VRRGKTLJSA-N (3ar,5r,6s,7r,7ar)-5-(hydroxymethyl)-2-propan-2-yl-5,6,7,7a-tetrahydro-3ah-pyrano[3,2-d][1,3]thiazole-6,7-diol Chemical compound S1C(C(C)C)=N[C@H]2[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]2O FOOVVGIBHSAEPH-VRRGKTLJSA-N 0.000 claims 3
- QWOPEBCGKASVQP-QXOHVQIXSA-N (3ar,5r,6s,7r,7ar)-5-(hydroxymethyl)-2-propyl-5,6,7,7a-tetrahydro-3ah-pyrano[3,2-d][1,3]thiazole-6,7-diol Chemical compound S1C(CCC)=N[C@H]2[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]2O QWOPEBCGKASVQP-QXOHVQIXSA-N 0.000 claims 3
- 101001120790 Caenorhabditis elegans UDP-N-acetylglucosamine-peptide N-acetylglucosaminyltransferase Proteins 0.000 claims 3
- 239000003814 drug Substances 0.000 claims 3
- 230000003028 elevating effect Effects 0.000 claims 3
- 102000005744 Glycoside Hydrolases Human genes 0.000 abstract description 47
- 108010031186 Glycoside Hydrolases Proteins 0.000 abstract description 47
- 238000009825 accumulation Methods 0.000 abstract description 10
- 230000007812 deficiency Effects 0.000 abstract description 8
- 208000037765 diseases and disorders Diseases 0.000 abstract description 8
- 238000010171 animal model Methods 0.000 abstract description 7
- 230000002018 overexpression Effects 0.000 abstract description 5
- 102000004190 Enzymes Human genes 0.000 description 44
- 108090000790 Enzymes Proteins 0.000 description 44
- 210000004027 cell Anatomy 0.000 description 44
- 229940088598 enzyme Drugs 0.000 description 44
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 44
- 108090000623 proteins and genes Proteins 0.000 description 43
- 239000000243 solution Substances 0.000 description 43
- 102000004169 proteins and genes Human genes 0.000 description 39
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 37
- 241000700159 Rattus Species 0.000 description 37
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 36
- ZSJLQEPLLKMAKR-GKHCUFPYSA-N streptozocin Chemical compound O=NN(C)C(=O)N[C@H]1[C@@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O ZSJLQEPLLKMAKR-GKHCUFPYSA-N 0.000 description 36
- ZSJLQEPLLKMAKR-UHFFFAOYSA-N Streptozotocin Natural products O=NN(C)C(=O)NC1C(O)OC(CO)C(O)C1O ZSJLQEPLLKMAKR-UHFFFAOYSA-N 0.000 description 32
- 125000000217 alkyl group Chemical group 0.000 description 32
- 230000015572 biosynthetic process Effects 0.000 description 32
- 229960001052 streptozocin Drugs 0.000 description 32
- 210000001519 tissue Anatomy 0.000 description 32
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 31
- 239000000758 substrate Substances 0.000 description 31
- 238000004458 analytical method Methods 0.000 description 29
- PBLNJFVQMUMOJY-JXZOILRNSA-N [(z)-[(3r,4r,5s,6r)-3-acetamido-4,5-dihydroxy-6-(hydroxymethyl)oxan-2-ylidene]amino] n-phenylcarbamate Chemical compound CC(=O)N[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O\C1=N/OC(=O)NC1=CC=CC=C1 PBLNJFVQMUMOJY-JXZOILRNSA-N 0.000 description 28
- 230000007246 mechanism Effects 0.000 description 28
- 238000003556 assay Methods 0.000 description 27
- 238000006243 chemical reaction Methods 0.000 description 26
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 25
- 238000003786 synthesis reaction Methods 0.000 description 25
- DRHXTSWSUAJOJZ-FMDGEEDCSA-N (3ar,5r,6s,7r,7ar)-5-(hydroxymethyl)-2-methyl-5,6,7,7a-tetrahydro-3ah-pyrano[3,2-d][1,3]thiazole-6,7-diol Chemical compound S1C(C)=N[C@H]2[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]2O DRHXTSWSUAJOJZ-FMDGEEDCSA-N 0.000 description 24
- 230000001413 cellular effect Effects 0.000 description 24
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 23
- 230000000694 effects Effects 0.000 description 23
- 102000013498 tau Proteins Human genes 0.000 description 23
- 108010026424 tau Proteins Proteins 0.000 description 23
- 238000001262 western blot Methods 0.000 description 23
- 125000005842 heteroatom Chemical group 0.000 description 22
- 239000000203 mixture Substances 0.000 description 19
- 101150041968 CDC13 gene Proteins 0.000 description 18
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 18
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 18
- 239000000872 buffer Substances 0.000 description 18
- 108091005573 modified proteins Proteins 0.000 description 18
- 102000035118 modified proteins Human genes 0.000 description 18
- 238000002347 injection Methods 0.000 description 17
- 239000007924 injection Substances 0.000 description 17
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 17
- YQHOHPOCZUAUKP-UHFFFAOYSA-N n-[(aminooxy)carbonyl]aniline Chemical compound NOC(=O)NC1=CC=CC=C1 YQHOHPOCZUAUKP-UHFFFAOYSA-N 0.000 description 17
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 16
- 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 16
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 16
- 125000003118 aryl group Chemical group 0.000 description 16
- 210000004556 brain Anatomy 0.000 description 16
- 230000003197 catalytic effect Effects 0.000 description 16
- 125000000753 cycloalkyl group Chemical group 0.000 description 16
- 239000008103 glucose Substances 0.000 description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 15
- 150000001408 amides Chemical class 0.000 description 15
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 14
- 230000006870 function Effects 0.000 description 14
- 239000002904 solvent Substances 0.000 description 14
- CBDKQYKMCICBOF-UHFFFAOYSA-N thiazoline Chemical compound C1CN=CS1 CBDKQYKMCICBOF-UHFFFAOYSA-N 0.000 description 14
- 238000005481 NMR spectroscopy Methods 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 150000002148 esters Chemical class 0.000 description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 11
- 125000002252 acyl group Chemical group 0.000 description 11
- 238000002474 experimental method Methods 0.000 description 11
- 239000000543 intermediate Substances 0.000 description 11
- 230000002132 lysosomal effect Effects 0.000 description 11
- 238000012986 modification Methods 0.000 description 11
- 230000003389 potentiating effect Effects 0.000 description 11
- 230000036962 time dependent Effects 0.000 description 11
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 10
- 238000005160 1H NMR spectroscopy Methods 0.000 description 10
- 102000002268 Hexosaminidases Human genes 0.000 description 10
- 108010000540 Hexosaminidases Proteins 0.000 description 10
- 230000000903 blocking effect Effects 0.000 description 10
- 230000001965 increasing effect Effects 0.000 description 10
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 10
- 239000012528 membrane Substances 0.000 description 10
- 210000003205 muscle Anatomy 0.000 description 10
- 239000000047 product Substances 0.000 description 10
- 239000011541 reaction mixture Substances 0.000 description 10
- PSGQCCSGKGJLRL-UHFFFAOYSA-N 4-methyl-2h-chromen-2-one Chemical group C1=CC=CC2=C1OC(=O)C=C2C PSGQCCSGKGJLRL-UHFFFAOYSA-N 0.000 description 9
- HSHNITRMYYLLCV-UHFFFAOYSA-N 4-methylumbelliferone Chemical compound C1=C(O)C=CC2=C1OC(=O)C=C2C HSHNITRMYYLLCV-UHFFFAOYSA-N 0.000 description 9
- 241001465754 Metazoa Species 0.000 description 9
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 9
- 150000001412 amines Chemical class 0.000 description 9
- 201000010099 disease Diseases 0.000 description 9
- 230000004048 modification Effects 0.000 description 9
- -1 oxazolinium ion Chemical class 0.000 description 9
- 210000003462 vein Anatomy 0.000 description 9
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
- 108091006629 SLC13A2 Proteins 0.000 description 8
- 238000011161 development Methods 0.000 description 8
- 230000018109 developmental process Effects 0.000 description 8
- 150000002170 ethers Chemical class 0.000 description 8
- 239000000284 extract Substances 0.000 description 8
- 230000026731 phosphorylation Effects 0.000 description 8
- 238000006366 phosphorylation reaction Methods 0.000 description 8
- 238000000746 purification Methods 0.000 description 8
- 150000003549 thiazolines Chemical class 0.000 description 8
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 7
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 7
- 239000008280 blood Substances 0.000 description 7
- 210000004369 blood Anatomy 0.000 description 7
- 238000013461 design Methods 0.000 description 7
- 238000003818 flash chromatography Methods 0.000 description 7
- 230000006951 hyperphosphorylation Effects 0.000 description 7
- 238000012417 linear regression Methods 0.000 description 7
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 7
- 235000019341 magnesium sulphate Nutrition 0.000 description 7
- 210000002682 neurofibrillary tangle Anatomy 0.000 description 7
- 150000002923 oximes Chemical class 0.000 description 7
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 6
- 150000001298 alcohols Chemical class 0.000 description 6
- 150000001299 aldehydes Chemical class 0.000 description 6
- 210000005013 brain tissue Anatomy 0.000 description 6
- 150000004657 carbamic acid derivatives Chemical class 0.000 description 6
- 235000013877 carbamide Nutrition 0.000 description 6
- 150000001735 carboxylic acids Chemical class 0.000 description 6
- 238000004587 chromatography analysis Methods 0.000 description 6
- 125000001153 fluoro group Chemical group F* 0.000 description 6
- 230000007062 hydrolysis Effects 0.000 description 6
- 238000006460 hydrolysis reaction Methods 0.000 description 6
- 230000002779 inactivation Effects 0.000 description 6
- 238000001990 intravenous administration Methods 0.000 description 6
- 239000000463 material Substances 0.000 description 6
- 102220095304 rs876659980 Human genes 0.000 description 6
- 239000000377 silicon dioxide Substances 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- 150000003672 ureas Chemical class 0.000 description 6
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 5
- 108010053345 Hexosaminidase B Proteins 0.000 description 5
- 102000016870 Hexosaminidase B Human genes 0.000 description 5
- 102000004877 Insulin Human genes 0.000 description 5
- 108090001061 Insulin Proteins 0.000 description 5
- 206010022489 Insulin Resistance Diseases 0.000 description 5
- 230000009471 action Effects 0.000 description 5
- 238000001514 detection method Methods 0.000 description 5
- 229930182470 glycoside Natural products 0.000 description 5
- 150000002338 glycosides Chemical class 0.000 description 5
- 229940125396 insulin Drugs 0.000 description 5
- 210000000496 pancreas Anatomy 0.000 description 5
- 230000035945 sensitivity Effects 0.000 description 5
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 5
- 230000007704 transition Effects 0.000 description 5
- IMSODMZESSGVBE-UHFFFAOYSA-N 2-Oxazoline Chemical compound C1CN=CO1 IMSODMZESSGVBE-UHFFFAOYSA-N 0.000 description 4
- BUBVLQDEIIUIQG-UHFFFAOYSA-N 3,4,5-tris(phenylmethoxy)-6-(phenylmethoxymethyl)oxan-2-one Chemical compound C=1C=CC=CC=1COC1C(OCC=2C=CC=CC=2)C(OCC=2C=CC=CC=2)C(=O)OC1COCC1=CC=CC=C1 BUBVLQDEIIUIQG-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 4
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 4
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
- 108091023040 Transcription factor Proteins 0.000 description 4
- 102000040945 Transcription factor Human genes 0.000 description 4
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 description 4
- 150000001263 acyl chlorides Chemical class 0.000 description 4
- 125000002619 bicyclic group Chemical group 0.000 description 4
- 238000001460 carbon-13 nuclear magnetic resonance spectrum Methods 0.000 description 4
- 125000006355 carbonyl methylene group Chemical group [H]C([H])([*:2])C([*:1])=O 0.000 description 4
- 230000002860 competitive effect Effects 0.000 description 4
- 238000000354 decomposition reaction Methods 0.000 description 4
- 238000006911 enzymatic reaction Methods 0.000 description 4
- 235000019197 fats Nutrition 0.000 description 4
- 229910052731 fluorine Inorganic materials 0.000 description 4
- 239000011737 fluorine Substances 0.000 description 4
- 235000013305 food Nutrition 0.000 description 4
- 238000007446 glucose tolerance test Methods 0.000 description 4
- 150000002373 hemiacetals Chemical class 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 235000019799 monosodium phosphate Nutrition 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- 230000037361 pathway Effects 0.000 description 4
- YBYRMVIVWMBXKQ-UHFFFAOYSA-N phenylmethanesulfonyl fluoride Chemical compound FS(=O)(=O)CC1=CC=CC=C1 YBYRMVIVWMBXKQ-UHFFFAOYSA-N 0.000 description 4
- RGCLLPNLLBQHPF-HJWRWDBZSA-N phosphamidon Chemical compound CCN(CC)C(=O)C(\Cl)=C(/C)OP(=O)(OC)OC RGCLLPNLLBQHPF-HJWRWDBZSA-N 0.000 description 4
- 230000004481 post-translational protein modification Effects 0.000 description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 4
- 230000001105 regulatory effect Effects 0.000 description 4
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 4
- 229910000162 sodium phosphate Inorganic materials 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 210000000952 spleen Anatomy 0.000 description 4
- 125000001424 substituent group Chemical group 0.000 description 4
- 238000006467 substitution reaction Methods 0.000 description 4
- KZNICNPSHKQLFF-UHFFFAOYSA-N succinimide Chemical compound O=C1CCC(=O)N1 KZNICNPSHKQLFF-UHFFFAOYSA-N 0.000 description 4
- 150000003556 thioamides Chemical class 0.000 description 4
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 3
- 238000004293 19F NMR spectroscopy Methods 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- 241000283707 Capra Species 0.000 description 3
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- 108010053317 Hexosaminidase A Proteins 0.000 description 3
- 102000016871 Hexosaminidase A Human genes 0.000 description 3
- 241000282412 Homo Species 0.000 description 3
- 108010044467 Isoenzymes Proteins 0.000 description 3
- OVRNDRQMDRJTHS-RTRLPJTCSA-N N-acetyl-D-glucosamine Chemical compound CC(=O)N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O OVRNDRQMDRJTHS-RTRLPJTCSA-N 0.000 description 3
- 102100041030 Pancreas/duodenum homeobox protein 1 Human genes 0.000 description 3
- 101710144033 Pancreas/duodenum homeobox protein 1 Proteins 0.000 description 3
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 3
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical class [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000007983 Tris buffer Substances 0.000 description 3
- 238000006640 acetylation reaction Methods 0.000 description 3
- 210000004958 brain cell Anatomy 0.000 description 3
- 239000012267 brine Substances 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 238000004113 cell culture Methods 0.000 description 3
- 230000003247 decreasing effect Effects 0.000 description 3
- 238000006073 displacement reaction Methods 0.000 description 3
- 230000004064 dysfunction Effects 0.000 description 3
- 238000000921 elemental analysis Methods 0.000 description 3
- 125000000816 ethylene group Chemical group [H]C([H])([*:1])C([H])([H])[*:2] 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 230000002427 irreversible effect Effects 0.000 description 3
- 239000010410 layer Substances 0.000 description 3
- 210000004185 liver Anatomy 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- 239000012038 nucleophile Substances 0.000 description 3
- 230000002093 peripheral effect Effects 0.000 description 3
- DGTNSSLYPYDJGL-UHFFFAOYSA-N phenyl isocyanate Chemical compound O=C=NC1=CC=CC=C1 DGTNSSLYPYDJGL-UHFFFAOYSA-N 0.000 description 3
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 description 3
- 230000001737 promoting effect Effects 0.000 description 3
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 3
- 238000012453 sprague-dawley rat model Methods 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 230000003335 steric effect Effects 0.000 description 3
- 230000035882 stress Effects 0.000 description 3
- 239000006188 syrup Substances 0.000 description 3
- 235000020357 syrup Nutrition 0.000 description 3
- 125000000341 threoninyl group Chemical group [H]OC([H])(C([H])([H])[H])C([H])(N([H])[H])C(*)=O 0.000 description 3
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 3
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 2
- WDYVUKGVKRZQNM-UHFFFAOYSA-N 6-phosphonohexylphosphonic acid Chemical compound OP(O)(=O)CCCCCCP(O)(O)=O WDYVUKGVKRZQNM-UHFFFAOYSA-N 0.000 description 2
- 102100022549 Beta-hexosaminidase subunit beta Human genes 0.000 description 2
- 229940126657 Compound 17 Drugs 0.000 description 2
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 2
- LLQPHQFNMLZJMP-UHFFFAOYSA-N Fentrazamide Chemical compound N1=NN(C=2C(=CC=CC=2)Cl)C(=O)N1C(=O)N(CC)C1CCCCC1 LLQPHQFNMLZJMP-UHFFFAOYSA-N 0.000 description 2
- 239000004471 Glycine Substances 0.000 description 2
- XLYOFNOQVPJJNP-ZSJDYOACSA-N Heavy water Chemical compound [2H]O[2H] XLYOFNOQVPJJNP-ZSJDYOACSA-N 0.000 description 2
- 101001045433 Homo sapiens Beta-hexosaminidase subunit beta Proteins 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 2
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 2
- 231100000757 Microbial toxin Toxicity 0.000 description 2
- 241000699666 Mus <mouse, genus> Species 0.000 description 2
- 229910017912 NH2OH Inorganic materials 0.000 description 2
- MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical compound O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 description 2
- 108091000080 Phosphotransferase Proteins 0.000 description 2
- 102000012338 Poly(ADP-ribose) Polymerases Human genes 0.000 description 2
- 108010061844 Poly(ADP-ribose) Polymerases Proteins 0.000 description 2
- 229920000776 Poly(Adenosine diphosphate-ribose) polymerase Polymers 0.000 description 2
- 108010029485 Protein Isoforms Proteins 0.000 description 2
- 102000001708 Protein Isoforms Human genes 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 102000001435 Synapsin Human genes 0.000 description 2
- 108050009621 Synapsin Proteins 0.000 description 2
- MJOQJPYNENPSSS-XQHKEYJVSA-N [(3r,4s,5r,6s)-4,5,6-triacetyloxyoxan-3-yl] acetate Chemical compound CC(=O)O[C@@H]1CO[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O MJOQJPYNENPSSS-XQHKEYJVSA-N 0.000 description 2
- 210000001789 adipocyte Anatomy 0.000 description 2
- 125000001931 aliphatic group Chemical group 0.000 description 2
- 235000012501 ammonium carbonate Nutrition 0.000 description 2
- 206010002026 amyotrophic lateral sclerosis Diseases 0.000 description 2
- 239000004599 antimicrobial Substances 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 239000003637 basic solution Substances 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 230000015556 catabolic process Effects 0.000 description 2
- 238000006555 catalytic reaction Methods 0.000 description 2
- 230000024245 cell differentiation Effects 0.000 description 2
- 230000005754 cellular signaling Effects 0.000 description 2
- 230000004637 cellular stress Effects 0.000 description 2
- 238000012512 characterization method Methods 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000010367 cloning Methods 0.000 description 2
- 230000006957 competitive inhibition Effects 0.000 description 2
- KXGVEGMKQFWNSR-LLQZFEROSA-N deoxycholic acid Chemical compound C([C@H]1CC2)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 KXGVEGMKQFWNSR-LLQZFEROSA-N 0.000 description 2
- 229960003964 deoxycholic acid Drugs 0.000 description 2
- 230000018514 detection of nutrient Effects 0.000 description 2
- 230000001627 detrimental effect Effects 0.000 description 2
- 235000005911 diet Nutrition 0.000 description 2
- 230000037213 diet Effects 0.000 description 2
- PBWZKZYHONABLN-UHFFFAOYSA-N difluoroacetic acid Chemical compound OC(=O)C(F)F PBWZKZYHONABLN-UHFFFAOYSA-N 0.000 description 2
- 238000001952 enzyme assay Methods 0.000 description 2
- QEWYKACRFQMRMB-UHFFFAOYSA-N fluoroacetic acid Chemical compound OC(=O)CF QEWYKACRFQMRMB-UHFFFAOYSA-N 0.000 description 2
- 230000014509 gene expression Effects 0.000 description 2
- 230000002068 genetic effect Effects 0.000 description 2
- 125000003147 glycosyl group Chemical group 0.000 description 2
- 238000009396 hybridization Methods 0.000 description 2
- 230000000937 inactivator Effects 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 230000003834 intracellular effect Effects 0.000 description 2
- 210000004731 jugular vein Anatomy 0.000 description 2
- CFHGBZLNZZVTAY-UHFFFAOYSA-N lawesson's reagent Chemical compound C1=CC(OC)=CC=C1P1(=S)SP(=S)(C=2C=CC(OC)=CC=2)S1 CFHGBZLNZZVTAY-UHFFFAOYSA-N 0.000 description 2
- 238000011068 loading method Methods 0.000 description 2
- 239000012139 lysis buffer Substances 0.000 description 2
- 210000003712 lysosome Anatomy 0.000 description 2
- 230000001868 lysosomic effect Effects 0.000 description 2
- 235000010335 lysozyme Nutrition 0.000 description 2
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Natural products C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 2
- 210000002569 neuron Anatomy 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 2
- 230000000269 nucleophilic effect Effects 0.000 description 2
- 235000015097 nutrients Nutrition 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- PFGVNLZDWRZPJW-OPAMFIHVSA-N otamixaban Chemical compound C([C@@H](C(=O)OC)[C@@H](C)NC(=O)C=1C=CC(=CC=1)C=1C=C[N+]([O-])=CC=1)C1=CC=CC(C(N)=N)=C1 PFGVNLZDWRZPJW-OPAMFIHVSA-N 0.000 description 2
- 235000015927 pasta Nutrition 0.000 description 2
- 102000020233 phosphotransferase Human genes 0.000 description 2
- 230000003169 placental effect Effects 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 2
- 238000010791 quenching Methods 0.000 description 2
- 230000000171 quenching effect Effects 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 239000011347 resin Substances 0.000 description 2
- 229920005989 resin Polymers 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 150000003384 small molecules Chemical class 0.000 description 2
- 230000003595 spectral effect Effects 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 229960002317 succinimide Drugs 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 238000012546 transfer Methods 0.000 description 2
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 2
- 150000004072 triols Chemical class 0.000 description 2
- 239000011534 wash buffer Substances 0.000 description 2
- MSWZFWKMSRAUBD-UHFFFAOYSA-N 2-Amino-2-Deoxy-Hexose Chemical compound NC1C(O)OC(CO)C(O)C1O MSWZFWKMSRAUBD-UHFFFAOYSA-N 0.000 description 1
- IOOWNWLVCOUUEX-WPRPVWTQSA-N 2-[(3r,6s)-2-hydroxy-3-[(2-thiophen-2-ylacetyl)amino]oxaborinan-6-yl]acetic acid Chemical compound OB1O[C@H](CC(O)=O)CC[C@@H]1NC(=O)CC1=CC=CS1 IOOWNWLVCOUUEX-WPRPVWTQSA-N 0.000 description 1
- PPSMYAUEJRADFE-HXUWFJFHSA-N 2-[(5r)-4-[2-[3-(6-methylpyridin-3-yl)oxyphenyl]acetyl]-8-(trifluoromethyl)-1,2,3,5-tetrahydropyrido[2,3-e][1,4]diazepin-5-yl]acetic acid Chemical compound C1=NC(C)=CC=C1OC1=CC=CC(CC(=O)N2[C@@H](C3=CC=C(N=C3NCC2)C(F)(F)F)CC(O)=O)=C1 PPSMYAUEJRADFE-HXUWFJFHSA-N 0.000 description 1
- MSWZFWKMSRAUBD-IVMDWMLBSA-N 2-amino-2-deoxy-D-glucopyranose Chemical compound N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O MSWZFWKMSRAUBD-IVMDWMLBSA-N 0.000 description 1
- BTJIUGUIPKRLHP-UHFFFAOYSA-N 4-nitrophenol Chemical compound OC1=CC=C([N+]([O-])=O)C=C1 BTJIUGUIPKRLHP-UHFFFAOYSA-N 0.000 description 1
- 241001149952 Amylomyces rouxii Species 0.000 description 1
- 241000272814 Anser sp. Species 0.000 description 1
- 101100277337 Arabidopsis thaliana DDM1 gene Proteins 0.000 description 1
- 241000228245 Aspergillus niger Species 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 238000009010 Bradford assay Methods 0.000 description 1
- QUMCIHKVKQYNPA-RUZDIDTESA-N C1(CCCCC1)CN1[C@@H](C=2N(C=3C=NC(=NC1=3)NC1=C(C=C(C(=O)NC3CCN(CC3)C)C=C1)OC)C(=NN=2)C)CC Chemical compound C1(CCCCC1)CN1[C@@H](C=2N(C=3C=NC(=NC1=3)NC1=C(C=C(C(=O)NC3CCN(CC3)C)C=C1)OC)C(=NN=2)C)CC QUMCIHKVKQYNPA-RUZDIDTESA-N 0.000 description 1
- 101100219382 Caenorhabditis elegans cah-2 gene Proteins 0.000 description 1
- 244000045232 Canavalia ensiformis Species 0.000 description 1
- 235000010520 Canavalia ensiformis Nutrition 0.000 description 1
- 206010011086 Coronary artery occlusion Diseases 0.000 description 1
- 102000010831 Cytoskeletal Proteins Human genes 0.000 description 1
- 108010037414 Cytoskeletal Proteins Proteins 0.000 description 1
- 108020004414 DNA Proteins 0.000 description 1
- 102000053602 DNA Human genes 0.000 description 1
- 206010012289 Dementia Diseases 0.000 description 1
- 208000031124 Dementia Alzheimer type Diseases 0.000 description 1
- 206010013082 Discomfort Diseases 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- 241000206602 Eukaryota Species 0.000 description 1
- JNCMHMUGTWEVOZ-UHFFFAOYSA-N F[CH]F Chemical compound F[CH]F JNCMHMUGTWEVOZ-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 201000011240 Frontotemporal dementia Diseases 0.000 description 1
- 229930186217 Glycolipid Natural products 0.000 description 1
- 108010081348 HRT1 protein Hairy Proteins 0.000 description 1
- 102100021881 Hairy/enhancer-of-split related with YRPW motif protein 1 Human genes 0.000 description 1
- 102000003893 Histone acetyltransferases Human genes 0.000 description 1
- 108090000246 Histone acetyltransferases Proteins 0.000 description 1
- 101001045440 Homo sapiens Beta-hexosaminidase subunit alpha Proteins 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- PIWKPBJCKXDKJR-UHFFFAOYSA-N Isoflurane Chemical compound FC(F)OC(Cl)C(F)(F)F PIWKPBJCKXDKJR-UHFFFAOYSA-N 0.000 description 1
- 102000029749 Microtubule Human genes 0.000 description 1
- 108091022875 Microtubule Proteins 0.000 description 1
- 102000016943 Muramidase Human genes 0.000 description 1
- 108010014251 Muramidase Proteins 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 108010062010 N-Acetylmuramoyl-L-alanine Amidase Proteins 0.000 description 1
- 125000003047 N-acetyl group Chemical group 0.000 description 1
- 229940122373 N-acetyl-glucosaminidase inhibitor Drugs 0.000 description 1
- BAWFJGJZGIEFAR-NNYOXOHSSA-O NAD(+) Chemical compound NC(=O)C1=CC=C[N+]([C@H]2[C@@H]([C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OC[C@@H]3[C@H]([C@@H](O)[C@@H](O3)N3C4=NC=NC(N)=C4N=C3)O)O2)O)=C1 BAWFJGJZGIEFAR-NNYOXOHSSA-O 0.000 description 1
- 208000012902 Nervous system disease Diseases 0.000 description 1
- 102000008763 Neurofilament Proteins Human genes 0.000 description 1
- 108010088373 Neurofilament Proteins Proteins 0.000 description 1
- 101100519293 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) pdx-1 gene Proteins 0.000 description 1
- 239000000020 Nitrocellulose Substances 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 102000004160 Phosphoric Monoester Hydrolases Human genes 0.000 description 1
- 108090000608 Phosphoric Monoester Hydrolases Proteins 0.000 description 1
- 208000000609 Pick Disease of the Brain Diseases 0.000 description 1
- 229920001213 Polysorbate 20 Polymers 0.000 description 1
- 241000786363 Rhampholeon spectrum Species 0.000 description 1
- 241000283984 Rodentia Species 0.000 description 1
- 208000021811 Sandhoff disease Diseases 0.000 description 1
- 101710172711 Structural protein Proteins 0.000 description 1
- 102000004357 Transferases Human genes 0.000 description 1
- 108090000992 Transferases Proteins 0.000 description 1
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 description 1
- 208000007930 Type C Niemann-Pick Disease Diseases 0.000 description 1
- LFTYTUAZOPRMMI-UHFFFAOYSA-N UNPD164450 Natural products O1C(CO)C(O)C(O)C(NC(=O)C)C1OP(O)(=O)OP(O)(=O)OCC1C(O)C(O)C(N2C(NC(=O)C=C2)=O)O1 LFTYTUAZOPRMMI-UHFFFAOYSA-N 0.000 description 1
- 102000005456 Vesicular Transport Adaptor Proteins Human genes 0.000 description 1
- 108010031770 Vesicular Transport Adaptor Proteins Proteins 0.000 description 1
- NPUXORBZRBIOMQ-RUZDIDTESA-N [(2R)-1-[[4-[[3-(benzenesulfonylmethyl)-5-methylphenoxy]methyl]phenyl]methyl]-2-pyrrolidinyl]methanol Chemical compound C=1C(OCC=2C=CC(CN3[C@H](CCC3)CO)=CC=2)=CC(C)=CC=1CS(=O)(=O)C1=CC=CC=C1 NPUXORBZRBIOMQ-RUZDIDTESA-N 0.000 description 1
- ZRAWPYYLRZSVEU-GNMOMJPPSA-N [(2r,3s,4r,5r)-3,4,6-triacetyloxy-5-aminooxan-2-yl]methyl acetate Chemical compound CC(=O)OC[C@H]1OC(OC(C)=O)[C@H](N)[C@@H](OC(C)=O)[C@@H]1OC(C)=O ZRAWPYYLRZSVEU-GNMOMJPPSA-N 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 230000002730 additional effect Effects 0.000 description 1
- 230000004931 aggregating effect Effects 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 125000000539 amino acid group Chemical group 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 235000018660 ammonium molybdate Nutrition 0.000 description 1
- 239000011609 ammonium molybdate Substances 0.000 description 1
- APUPEJJSWDHEBO-UHFFFAOYSA-P ammonium molybdate Chemical compound [NH4+].[NH4+].[O-][Mo]([O-])(=O)=O APUPEJJSWDHEBO-UHFFFAOYSA-P 0.000 description 1
- 229940010552 ammonium molybdate Drugs 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000031018 biological processes and functions Effects 0.000 description 1
- 230000006696 biosynthetic metabolic pathway Effects 0.000 description 1
- 238000010241 blood sampling Methods 0.000 description 1
- 239000000337 buffer salt Substances 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 230000000981 bystander Effects 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 230000030833 cell death Effects 0.000 description 1
- 230000003915 cell function Effects 0.000 description 1
- 108091092356 cellular DNA Proteins 0.000 description 1
- 230000033077 cellular process Effects 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 101150113676 chr1 gene Proteins 0.000 description 1
- 230000002759 chromosomal effect Effects 0.000 description 1
- 238000010835 comparative analysis Methods 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 210000004748 cultured cell Anatomy 0.000 description 1
- 230000001086 cytosolic effect Effects 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 230000002939 deleterious effect Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 230000000779 depleting effect Effects 0.000 description 1
- 230000001904 diabetogenic effect Effects 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 238000001962 electrophoresis Methods 0.000 description 1
- 210000000750 endocrine system Anatomy 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical class CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 1
- UREBWPXBXRYXRJ-UHFFFAOYSA-N ethyl acetate;methanol Chemical compound OC.CCOC(C)=O UREBWPXBXRYXRJ-UHFFFAOYSA-N 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 230000003631 expected effect Effects 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000000806 fluorine-19 nuclear magnetic resonance spectrum Methods 0.000 description 1
- VUWZPRWSIVNGKG-UHFFFAOYSA-N fluoromethane Chemical compound F[CH2] VUWZPRWSIVNGKG-UHFFFAOYSA-N 0.000 description 1
- 150000002270 gangliosides Chemical class 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 230000014101 glucose homeostasis Effects 0.000 description 1
- 238000003306 harvesting Methods 0.000 description 1
- 238000000265 homogenisation Methods 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 230000001900 immune effect Effects 0.000 description 1
- 230000001976 improved effect Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 229960002725 isoflurane Drugs 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 238000012933 kinetic analysis Methods 0.000 description 1
- 150000002596 lactones Chemical class 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 210000005228 liver tissue Anatomy 0.000 description 1
- 239000012160 loading buffer Substances 0.000 description 1
- 230000033001 locomotion Effects 0.000 description 1
- 235000004213 low-fat Nutrition 0.000 description 1
- 239000004325 lysozyme Substances 0.000 description 1
- 229960000274 lysozyme Drugs 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 210000004688 microtubule Anatomy 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- 230000003278 mimic effect Effects 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 150000002772 monosaccharides Chemical class 0.000 description 1
- 239000004570 mortar (masonry) Substances 0.000 description 1
- 239000006225 natural substrate Substances 0.000 description 1
- 229920001220 nitrocellulos Polymers 0.000 description 1
- ZHCAAFJSYLFLPX-UHFFFAOYSA-N nitrocyclohexatriene Chemical group [O-][N+](=O)C1=CC=C=C[CH]1 ZHCAAFJSYLFLPX-UHFFFAOYSA-N 0.000 description 1
- 229910000069 nitrogen hydride Inorganic materials 0.000 description 1
- 239000012740 non-selective inhibitor Substances 0.000 description 1
- 239000002773 nucleotide Substances 0.000 description 1
- 125000003729 nucleotide group Chemical group 0.000 description 1
- 230000035764 nutrition Effects 0.000 description 1
- 235000016709 nutrition Nutrition 0.000 description 1
- 150000002482 oligosaccharides Polymers 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 244000052769 pathogen Species 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 238000002264 polyacrylamide gel electrophoresis Methods 0.000 description 1
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 1
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
- 102000035123 post-translationally modified proteins Human genes 0.000 description 1
- 108091005626 post-translationally modified proteins Proteins 0.000 description 1
- 235000015320 potassium carbonate Nutrition 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 235000008476 powdered milk Nutrition 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 230000004063 proteosomal degradation Effects 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 239000011369 resultant mixture Substances 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 238000006798 ring closing metathesis reaction Methods 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 238000007790 scraping Methods 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- PPASLZSBLFJQEF-RKJRWTFHSA-M sodium ascorbate Substances [Na+].OC[C@@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RKJRWTFHSA-M 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 1
- JGFYQVQAXANWJU-UHFFFAOYSA-M sodium fluoroacetate Chemical compound [Na+].[O-]C(=O)CF JGFYQVQAXANWJU-UHFFFAOYSA-M 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000010183 spectrum analysis Methods 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 239000012258 stirred mixture Substances 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 230000008093 supporting effect Effects 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 230000009897 systematic effect Effects 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- DKVBOUDTNWVDEP-NJCHZNEYSA-N teicoplanin aglycone Chemical compound N([C@H](C(N[C@@H](C1=CC(O)=CC(O)=C1C=1C(O)=CC=C2C=1)C(O)=O)=O)[C@H](O)C1=CC=C(C(=C1)Cl)OC=1C=C3C=C(C=1O)OC1=CC=C(C=C1Cl)C[C@H](C(=O)N1)NC([C@H](N)C=4C=C(O5)C(O)=CC=4)=O)C(=O)[C@@H]2NC(=O)[C@@H]3NC(=O)[C@@H]1C1=CC5=CC(O)=C1 DKVBOUDTNWVDEP-NJCHZNEYSA-N 0.000 description 1
- 125000002769 thiazolinyl group Chemical group 0.000 description 1
- 230000000451 tissue damage Effects 0.000 description 1
- 231100000827 tissue damage Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 230000001052 transient effect Effects 0.000 description 1
- 125000000430 tryptophan group Chemical group [H]N([H])C(C(=O)O*)C([H])([H])C1=C([H])N([H])C2=C([H])C([H])=C([H])C([H])=C12 0.000 description 1
- 230000003827 upregulation Effects 0.000 description 1
- LFTYTUAZOPRMMI-LSIJYXAZSA-N uridine-diphosphate-n-acetylglucosamine Chemical compound O1[C@@H](CO)[C@H](O)[C@@H](O)[C@H](NC(=O)C)[C@@H]1O[P@](O)(=O)O[P@](O)(=O)OC[C@H]1[C@H](O)[C@@H](O)[C@H](N2C(NC(=O)C=C2)=O)O1 LFTYTUAZOPRMMI-LSIJYXAZSA-N 0.000 description 1
- JQSHBVHOMNKWFT-DTORHVGOSA-N varenicline Chemical compound C12=CC3=NC=CN=C3C=C2[C@H]2C[C@@H]1CNC2 JQSHBVHOMNKWFT-DTORHVGOSA-N 0.000 description 1
- 238000011179 visual inspection Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- DGVVWUTYPXICAM-UHFFFAOYSA-N β‐Mercaptoethanol Chemical compound OCCS DGVVWUTYPXICAM-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
-
- 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
- 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
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Animal Behavior & Ethology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Biomedical Technology (AREA)
- Diabetes (AREA)
- Neurosurgery (AREA)
- Neurology (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Biotechnology (AREA)
- Genetics & Genomics (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Hospice & Palliative Care (AREA)
- Emergency Medicine (AREA)
- Endocrinology (AREA)
- Psychiatry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Saccharide Compounds (AREA)
- Pyrane Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA2819464A CA2819464A1 (en) | 2005-03-01 | 2006-03-01 | Selective glycosidase inhibitors, methods of making inhibitors, and uses thereof |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US65687805P | 2005-03-01 | 2005-03-01 | |
| US60/656,878 | 2005-03-01 | ||
| PCT/CA2006/000300 WO2006092049A1 (en) | 2005-03-01 | 2006-03-01 | Selective glycosidase inhibitors, methods of making inhibitors, and uses thereof |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA2819464A Division CA2819464A1 (en) | 2005-03-01 | 2006-03-01 | Selective glycosidase inhibitors, methods of making inhibitors, and uses thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2599843A1 CA2599843A1 (en) | 2006-09-08 |
| CA2599843C true CA2599843C (en) | 2013-08-27 |
Family
ID=36940808
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA2599843A Expired - Fee Related CA2599843C (en) | 2005-03-01 | 2006-03-01 | Selective glycosidase inhibitors, methods of making inhibitors, and uses thereof |
| CA2819464A Abandoned CA2819464A1 (en) | 2005-03-01 | 2006-03-01 | Selective glycosidase inhibitors, methods of making inhibitors, and uses thereof |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA2819464A Abandoned CA2819464A1 (en) | 2005-03-01 | 2006-03-01 | Selective glycosidase inhibitors, methods of making inhibitors, and uses thereof |
Country Status (7)
| Country | Link |
|---|---|
| US (1) | US20080287375A1 (OSRAM) |
| EP (2) | EP1869060B1 (OSRAM) |
| JP (1) | JP5154954B2 (OSRAM) |
| CN (1) | CN101208352B (OSRAM) |
| AU (1) | AU2006220187B2 (OSRAM) |
| CA (2) | CA2599843C (OSRAM) |
| WO (1) | WO2006092049A1 (OSRAM) |
Families Citing this family (48)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006016904A2 (en) * | 2004-04-14 | 2006-02-16 | Uab Research Foundation | Activators of hexosamine biosynthesis as inhibitors of injury induced by ischemia or hemorrhagic shock |
| CN101595111A (zh) * | 2006-08-31 | 2009-12-02 | 西蒙·弗雷瑟大学 | 选择性糖苷酶抑制剂及其用途 |
| CA2661582C (en) | 2006-08-31 | 2015-09-29 | Simon Fraser University | Selective glycosidase inhibitors and uses thereof |
| GB0622702D0 (en) * | 2006-11-15 | 2006-12-27 | Univ Dundee | Selective glycosidase inhibitors |
| US8518903B2 (en) | 2007-04-19 | 2013-08-27 | University of Pittsburgh—of the Commonwealth System of Higher Education | Use of toll-like receptor-9 agonists |
| JP2011529857A (ja) | 2008-08-01 | 2011-12-15 | サイモン フレイザー ユニバーシティ | 選択的グリコシダーゼインヒビターおよびその使用 |
| US9079868B2 (en) * | 2008-08-01 | 2015-07-14 | Simon Fraser University | Selective glycosidase inhibitors and uses thereof |
| AU2009299073B2 (en) * | 2008-09-16 | 2015-04-02 | Simon Fraser University | Selective glycosidase inhibitors and uses thereof |
| WO2011140640A1 (en) * | 2010-05-11 | 2011-11-17 | Simon Fraser University | Selective glycosidase inhibitors and uses thereof |
| US10668092B2 (en) | 2010-09-24 | 2020-06-02 | The John Hopkins University | Compositions and methods for treatment of inflammatory disorders |
| US9072760B2 (en) | 2010-09-24 | 2015-07-07 | University of Pittsburgh—of the Commonwealth System of Higher Education | TLR4 inhibitors for the treatment of human infectious and inflammatory disorders |
| WO2012040719A2 (en) * | 2010-09-24 | 2012-03-29 | University Of Pittsburgh - Of The Commonwealth System Of Higher Education | Novel tlr4 inhibitors for the treatment of human infectious and inflammatory disorders |
| WO2012061972A1 (en) * | 2010-11-08 | 2012-05-18 | Alectos Therapeutics Inc. | Selective glycosidase inhibitors and uses thereof |
| TW201249848A (en) | 2010-11-08 | 2012-12-16 | Merck Sharp & Dohme | Selective glycosidase inhibitors and uses thereof |
| US8933040B2 (en) | 2010-11-08 | 2015-01-13 | Craig A. Coburn | Selective glycosidase inhibitors and uses thereof |
| US8901087B2 (en) * | 2010-11-08 | 2014-12-02 | Merck Sharp & Dohme Corp. | Selective glycosidase inhibitors and uses thereof |
| WO2012088425A2 (en) | 2010-12-22 | 2012-06-28 | University Of Pittsburgh - Of The Commonwealth System Of Higher Education | Gap junction-enhancing agents for treatment of necrotizing enterocolitis and inflammatory bowel disease |
| LT2655388T (lt) | 2010-12-23 | 2016-11-10 | Alectos Therapeutics Inc. | Selektyvieji glikozidazės inhibitoriai ir jų panaudojimas |
| EP2688899B1 (en) | 2011-03-24 | 2017-02-22 | Alectos Therapeutics Inc. | Selective glycosidase inhibitors and uses thereof |
| WO2012129802A1 (en) * | 2011-03-31 | 2012-10-04 | Alectos Therapeutics Inc. | Pyrano[3,2-d]thiazol derivatives and uses as selective glycosidase inhibitors thereof |
| US9718854B2 (en) | 2011-03-31 | 2017-08-01 | Alectos Therapeutics Inc. | Selective glycosidase inhibitors and uses thereof |
| US9409924B2 (en) | 2011-06-27 | 2016-08-09 | Alectos Therapeutics Inc. | Selective glycosidase inhibitors and uses thereof |
| WO2013000085A1 (en) | 2011-06-27 | 2013-01-03 | Alectos Therapeutics Inc. | Selective glycosidase inhibitors and uses thereof |
| US9701693B2 (en) | 2011-06-27 | 2017-07-11 | Alectos Therapeutics Inc. | Selective glycosidase inhibitors and uses thereof |
| EP2744338B1 (en) * | 2011-08-18 | 2016-04-27 | Merck Sharp & Dohme Corp. | Selective glycosidase inhibitors and uses thereof |
| HUE029390T2 (en) * | 2011-08-25 | 2017-02-28 | Merck Patent Gmbh | Pirano [3,2-d] [1,3] thiazole derivatives as glucosidase inhibitors |
| RU2707292C2 (ru) * | 2012-05-08 | 2019-11-26 | Мерк Шарп И Доум Корп. | Проницаемые ингибиторы гликозидазы и их применения |
| WO2014032188A1 (en) | 2012-08-31 | 2014-03-06 | Alectos Therapeutics Inc. | Glycosidase inhibitors and uses thereof |
| US9670195B2 (en) | 2012-08-31 | 2017-06-06 | Alectos Therapeutics Inc. | Glycosidase inhibitors and uses thereof |
| WO2014052453A1 (en) | 2012-09-25 | 2014-04-03 | University Of Pittsburgh - Of The Commonwealth System Of Higher Education | Oral therapy of necrotizing enterocolitis |
| AU2013337570B2 (en) * | 2012-10-31 | 2018-01-18 | Alectos Therapeutics Inc. | Glycosidase inhibitors and uses thereof |
| WO2014100934A1 (en) * | 2012-12-24 | 2014-07-03 | Merck Sharp & Dohme Corp. | Glycosidase inhibitors and uses thereof |
| WO2014171206A1 (ja) * | 2013-04-17 | 2014-10-23 | Yuasa Tomoyuki | 糖尿病治療薬の新規なスクリーニング方法 |
| KR102043337B1 (ko) | 2014-08-28 | 2019-11-11 | 아셰뉴론 에스아 | 글리코시다제 저해제 |
| MA43677A (fr) | 2016-02-25 | 2018-11-28 | Asceneuron Sa | Inhibiteurs de glycosidases |
| MA43680A (fr) | 2016-02-25 | 2018-11-28 | Asceneuron Sa | Inhibiteurs de glycosidases |
| KR102800480B1 (ko) | 2016-02-25 | 2025-04-25 | 아셰뉴론 에스아 | 피페라진 유도체의 산 부가 염 |
| US11261183B2 (en) | 2016-02-25 | 2022-03-01 | Asceneuron Sa | Sulfoximine glycosidase inhibitors |
| EP3672959A1 (en) | 2017-08-24 | 2020-07-01 | Asceneuron SA | Linear glycosidase inhibitors |
| US12016852B2 (en) | 2018-08-22 | 2024-06-25 | Asceneuron Sa | Pyrrolidine glycosidase inhibitors |
| WO2020039029A1 (en) | 2018-08-22 | 2020-02-27 | Asceneuron S. A. | Spiro compounds as glycosidase inhibitors |
| SG11202101651RA (en) | 2018-08-22 | 2021-03-30 | Asceneuron S A | Succinate and fumarate acid addition salts of piperazine derivatives useful as glycosidase inhibitors |
| US11795165B2 (en) | 2018-08-22 | 2023-10-24 | Asceneuron Sa | Tetrahydro-benzoazepine glycosidase inhibitors |
| CN114524854B (zh) * | 2022-02-25 | 2023-05-26 | 中国农业大学 | 一种糖基芳香环碳苷衍生物及其制备方法与应用 |
| WO2024083820A1 (en) | 2022-10-18 | 2024-04-25 | Institut National de la Santé et de la Recherche Médicale | Method and composition for determining the level of o-glcnacylation in horses |
| CN116376875B (zh) * | 2023-03-03 | 2024-02-23 | 云南师范大学 | 耐热性提高的n-乙酰氨基葡萄糖苷酶突变体及其应用 |
| CN116555229B (zh) * | 2023-05-25 | 2024-09-20 | 云南师范大学 | N-乙酰氨基葡萄糖苷酶突变体、重组表达载体及菌和应用 |
| CN118086249B (zh) * | 2024-01-24 | 2024-12-06 | 云南师范大学 | 一种协同提高酶活和热稳定性的n-乙酰氨基葡萄糖苷酶突变体及其制备与应用 |
Family Cites Families (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB9818732D0 (en) * | 1998-08-27 | 1998-10-21 | Univ Portsmouth | Collection of compounds |
| US6774140B1 (en) * | 1999-05-11 | 2004-08-10 | The Scripps Research Institute | Iminocyclitol inhibitors of hexoaminidase and glycosidase |
| JP4036755B2 (ja) * | 2001-03-14 | 2008-01-23 | 電気化学工業株式会社 | ヒアルロン酸又はヒアルロン酸誘導体の製造法 |
| EP1633356A1 (en) * | 2003-05-22 | 2006-03-15 | The Hospital for Sick Children | Treatment of tay sachs or sandhoff diseases by enhancing hexosaminidase activity |
| CA2661582C (en) * | 2006-08-31 | 2015-09-29 | Simon Fraser University | Selective glycosidase inhibitors and uses thereof |
| US9079868B2 (en) * | 2008-08-01 | 2015-07-14 | Simon Fraser University | Selective glycosidase inhibitors and uses thereof |
| JP2011529857A (ja) * | 2008-08-01 | 2011-12-15 | サイモン フレイザー ユニバーシティ | 選択的グリコシダーゼインヒビターおよびその使用 |
| AU2009299073B2 (en) * | 2008-09-16 | 2015-04-02 | Simon Fraser University | Selective glycosidase inhibitors and uses thereof |
| WO2011140640A1 (en) * | 2010-05-11 | 2011-11-17 | Simon Fraser University | Selective glycosidase inhibitors and uses thereof |
| US8933040B2 (en) * | 2010-11-08 | 2015-01-13 | Craig A. Coburn | Selective glycosidase inhibitors and uses thereof |
| LT2655388T (lt) * | 2010-12-23 | 2016-11-10 | Alectos Therapeutics Inc. | Selektyvieji glikozidazės inhibitoriai ir jų panaudojimas |
| EP2688899B1 (en) * | 2011-03-24 | 2017-02-22 | Alectos Therapeutics Inc. | Selective glycosidase inhibitors and uses thereof |
| US9718854B2 (en) * | 2011-03-31 | 2017-08-01 | Alectos Therapeutics Inc. | Selective glycosidase inhibitors and uses thereof |
-
2006
- 2006-03-01 EP EP06705254A patent/EP1869060B1/en not_active Not-in-force
- 2006-03-01 AU AU2006220187A patent/AU2006220187B2/en not_active Ceased
- 2006-03-01 CA CA2599843A patent/CA2599843C/en not_active Expired - Fee Related
- 2006-03-01 CN CN2006800149950A patent/CN101208352B/zh not_active Expired - Fee Related
- 2006-03-01 JP JP2007557300A patent/JP5154954B2/ja not_active Expired - Fee Related
- 2006-03-01 US US11/817,465 patent/US20080287375A1/en not_active Abandoned
- 2006-03-01 WO PCT/CA2006/000300 patent/WO2006092049A1/en not_active Ceased
- 2006-03-01 CA CA2819464A patent/CA2819464A1/en not_active Abandoned
- 2006-03-01 EP EP11184538A patent/EP2436687A1/en not_active Withdrawn
Also Published As
| Publication number | Publication date |
|---|---|
| AU2006220187A1 (en) | 2006-09-08 |
| CN101208352A (zh) | 2008-06-25 |
| JP2008531604A (ja) | 2008-08-14 |
| EP1869060A4 (en) | 2009-08-12 |
| CN101208352B (zh) | 2013-08-07 |
| EP1869060B1 (en) | 2012-08-15 |
| JP5154954B2 (ja) | 2013-02-27 |
| EP1869060A1 (en) | 2007-12-26 |
| WO2006092049A1 (en) | 2006-09-08 |
| AU2006220187B2 (en) | 2012-11-08 |
| CA2819464A1 (en) | 2006-09-08 |
| EP2436687A1 (en) | 2012-04-04 |
| US20080287375A1 (en) | 2008-11-20 |
| CA2599843A1 (en) | 2006-09-08 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CA2599843C (en) | Selective glycosidase inhibitors, methods of making inhibitors, and uses thereof | |
| AU2007291870B2 (en) | Selective glycosidase inhibitors and uses thereof | |
| CA2816798C (en) | Selective glycosidase inhibitors and uses thereof | |
| Macauley et al. | O-GlcNAcase uses substrate-assisted catalysis: kineticanalysis and development of highly selective mechanism-inspiredinhibitors | |
| EP2935283B1 (en) | Glycosidase inhibitors and uses thereof | |
| AU2009276222B2 (en) | Selective glycosidase inhibitors and uses thereof | |
| WO2012061972A1 (en) | Selective glycosidase inhibitors and uses thereof | |
| CA2822493A1 (en) | Selective glycosidase inhibitors and uses thereof | |
| CA2732336A1 (en) | Selective glycosidase inhibitors and uses thereof | |
| CN107253970A (zh) | 选择性糖苷酶抑制剂及其用途 | |
| WO2012126091A1 (en) | Selective glycosidase inhibitors and uses thereof | |
| Ayers et al. | Nine of 16 stereoisomeric polyhydroxylated proline amides are potent β-N-acetylhexosaminidase inhibitors | |
| US8901087B2 (en) | Selective glycosidase inhibitors and uses thereof | |
| Aguilar-Moncayo et al. | Synthesis of thiohydantoin-castanospermine glycomimetics as glycosidase inhibitors | |
| AU2013200241A1 (en) | Selective glycosidase inhibitors, methods of making inhibitors, and uses thereof | |
| Kim | Studies towards finding selective substrates for human β-glucosidases |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| MKLA | Lapsed |
Effective date: 20180301 |
|
| MKLA | Lapsed |
Effective date: 20180301 |
|
| MKLA | Lapsed |
Effective date: 20180301 |