US20050171065A1 - Benzenedicarboxylic acid derivatives - Google Patents
Benzenedicarboxylic acid derivatives Download PDFInfo
- Publication number
- US20050171065A1 US20050171065A1 US11/051,188 US5118805A US2005171065A1 US 20050171065 A1 US20050171065 A1 US 20050171065A1 US 5118805 A US5118805 A US 5118805A US 2005171065 A1 US2005171065 A1 US 2005171065A1
- Authority
- US
- United States
- Prior art keywords
- compound
- mammal
- naaladase
- disease
- disorder
- 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.)
- Abandoned
Links
- XNGIFLGASWRNHJ-UHFFFAOYSA-N phthalic acid Chemical class OC(=O)C1=CC=CC=C1C(O)=O XNGIFLGASWRNHJ-UHFFFAOYSA-N 0.000 title description 5
- 150000001875 compounds Chemical class 0.000 claims abstract description 123
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 107
- 108090000369 Glutamate Carboxypeptidase II Proteins 0.000 claims abstract description 83
- 102000003958 Glutamate Carboxypeptidase II Human genes 0.000 claims abstract description 83
- 238000000034 method Methods 0.000 claims abstract description 76
- 201000010099 disease Diseases 0.000 claims abstract description 55
- 208000035475 disorder Diseases 0.000 claims abstract description 52
- 102000004887 Transforming Growth Factor beta Human genes 0.000 claims abstract description 33
- 108090001012 Transforming Growth Factor beta Proteins 0.000 claims abstract description 33
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 claims abstract description 32
- ZRKFYGHZFMAOKI-QMGMOQQFSA-N tgfbeta Chemical compound C([C@H](NC(=O)[C@H](C(C)C)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CCSC)C(C)C)[C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O)C1=CC=C(O)C=C1 ZRKFYGHZFMAOKI-QMGMOQQFSA-N 0.000 claims abstract description 32
- 229930195712 glutamate Natural products 0.000 claims abstract description 31
- 230000005856 abnormality Effects 0.000 claims abstract description 29
- 230000033115 angiogenesis Effects 0.000 claims abstract description 21
- 230000002401 inhibitory effect Effects 0.000 claims abstract description 21
- 208000002193 Pain Diseases 0.000 claims abstract description 16
- 230000001537 neural effect Effects 0.000 claims abstract description 16
- 230000036407 pain Effects 0.000 claims abstract description 16
- 208000033808 peripheral neuropathy Diseases 0.000 claims abstract description 16
- 208000017497 prostate disease Diseases 0.000 claims abstract description 13
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims abstract description 8
- 201000001119 neuropathy Diseases 0.000 claims abstract description 8
- 230000007823 neuropathy Effects 0.000 claims abstract description 8
- 238000009007 Diagnostic Kit Methods 0.000 claims abstract description 5
- 241001465754 Metazoa Species 0.000 claims description 45
- 241000124008 Mammalia Species 0.000 claims description 42
- 238000011282 treatment Methods 0.000 claims description 36
- 206010028980 Neoplasm Diseases 0.000 claims description 23
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 20
- 239000000126 substance Substances 0.000 claims description 17
- 201000011510 cancer Diseases 0.000 claims description 16
- 208000019901 Anxiety disease Diseases 0.000 claims description 15
- 125000005647 linker group Chemical group 0.000 claims description 15
- 210000001519 tissue Anatomy 0.000 claims description 15
- 208000006011 Stroke Diseases 0.000 claims description 14
- 230000006378 damage Effects 0.000 claims description 12
- 208000016192 Demyelinating disease Diseases 0.000 claims description 11
- 206010002026 amyotrophic lateral sclerosis Diseases 0.000 claims description 11
- 206010027175 memory impairment Diseases 0.000 claims description 11
- 208000018737 Parkinson disease Diseases 0.000 claims description 10
- 208000004296 neuralgia Diseases 0.000 claims description 10
- 208000021722 neuropathic pain Diseases 0.000 claims description 10
- 208000012902 Nervous system disease Diseases 0.000 claims description 9
- 230000004770 neurodegeneration Effects 0.000 claims description 9
- 201000000980 schizophrenia Diseases 0.000 claims description 8
- 239000011782 vitamin Substances 0.000 claims description 8
- 235000013343 vitamin Nutrition 0.000 claims description 8
- 229940088594 vitamin Drugs 0.000 claims description 8
- 229930003231 vitamin Natural products 0.000 claims description 8
- 210000004556 brain Anatomy 0.000 claims description 7
- 238000003384 imaging method Methods 0.000 claims description 7
- 208000007848 Alcoholism Diseases 0.000 claims description 6
- 201000007930 alcohol dependence Diseases 0.000 claims description 6
- 230000036506 anxiety Effects 0.000 claims description 6
- 239000003153 chemical reaction reagent Substances 0.000 claims description 6
- 206010013663 drug dependence Diseases 0.000 claims description 6
- BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 claims description 6
- 206010060862 Prostate cancer Diseases 0.000 claims description 5
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 claims description 5
- 239000012530 fluid Substances 0.000 claims description 5
- 210000002569 neuron Anatomy 0.000 claims description 5
- 208000001072 type 2 diabetes mellitus Diseases 0.000 claims description 5
- 208000022497 Cocaine-Related disease Diseases 0.000 claims description 4
- 206010057852 Nicotine dependence Diseases 0.000 claims description 4
- 208000025569 Tobacco Use disease Diseases 0.000 claims description 4
- 201000006145 cocaine dependence Diseases 0.000 claims description 4
- 239000003550 marker Substances 0.000 claims description 4
- 230000002265 prevention Effects 0.000 claims description 4
- 210000000278 spinal cord Anatomy 0.000 claims description 4
- 230000000638 stimulation Effects 0.000 claims description 4
- 208000030886 Traumatic Brain injury Diseases 0.000 claims description 3
- 230000006931 brain damage Effects 0.000 claims description 3
- 231100000874 brain damage Toxicity 0.000 claims description 3
- 208000029028 brain injury Diseases 0.000 claims description 3
- 238000002372 labelling Methods 0.000 claims description 3
- 229960005181 morphine Drugs 0.000 claims description 3
- 230000009529 traumatic brain injury Effects 0.000 claims description 3
- 150000003722 vitamin derivatives Chemical class 0.000 claims description 3
- 208000010877 cognitive disease Diseases 0.000 claims description 2
- 210000003734 kidney Anatomy 0.000 claims description 2
- 230000009689 neuronal regeneration Effects 0.000 claims description 2
- 210000001550 testis Anatomy 0.000 claims description 2
- -1 benzenedicarboxylic acid derivative compounds Chemical class 0.000 abstract description 65
- 230000000694 effects Effects 0.000 abstract description 42
- 208000010412 Glaucoma Diseases 0.000 abstract description 20
- 239000008194 pharmaceutical composition Substances 0.000 abstract description 8
- 238000002405 diagnostic procedure Methods 0.000 abstract description 3
- 206010012601 diabetes mellitus Diseases 0.000 description 52
- 241000700159 Rattus Species 0.000 description 48
- 239000003981 vehicle Substances 0.000 description 28
- 239000000203 mixture Substances 0.000 description 25
- 239000003112 inhibitor Substances 0.000 description 24
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 description 21
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 20
- 230000005764 inhibitory process Effects 0.000 description 17
- 125000003118 aryl group Chemical group 0.000 description 16
- 208000028867 ischemia Diseases 0.000 description 16
- 229940126062 Compound A Drugs 0.000 description 15
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 15
- 208000032131 Diabetic Neuropathies Diseases 0.000 description 14
- 125000001072 heteroaryl group Chemical group 0.000 description 14
- 208000014674 injury Diseases 0.000 description 14
- 230000007830 nerve conduction Effects 0.000 description 14
- 239000000243 solution Substances 0.000 description 14
- RGVICPPTAYWXEW-UHFFFAOYSA-N CC.C[Y].O=C(O)C1=CC=CC=C1 Chemical compound CC.C[Y].O=C(O)C1=CC=CC=C1 RGVICPPTAYWXEW-UHFFFAOYSA-N 0.000 description 13
- 125000000623 heterocyclic group Chemical group 0.000 description 13
- 238000002360 preparation method Methods 0.000 description 13
- 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 13
- OPVPGKGADVGKTG-BQBZGAKWSA-N Ac-Asp-Glu Chemical compound CC(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](C(O)=O)CCC(O)=O OPVPGKGADVGKTG-BQBZGAKWSA-N 0.000 description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 12
- CYWJBBPVDZBUAF-UHFFFAOYSA-N 4-(2-sulfanylethyl)benzene-1,3-dicarboxylic acid Chemical compound OC(=O)C1=CC=C(CCS)C(C(O)=O)=C1 CYWJBBPVDZBUAF-UHFFFAOYSA-N 0.000 description 10
- ATEDZEYFTCGZFE-UHFFFAOYSA-N 5-(phosphonomethyl)benzene-1,3-dicarboxylic acid Chemical compound OC(=O)C1=CC(CP(O)(O)=O)=CC(C(O)=O)=C1 ATEDZEYFTCGZFE-UHFFFAOYSA-N 0.000 description 10
- 241000223783 Glaucoma Species 0.000 description 10
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 10
- 239000002253 acid Substances 0.000 description 10
- 239000003814 drug Substances 0.000 description 10
- 235000019439 ethyl acetate Nutrition 0.000 description 10
- 230000012010 growth Effects 0.000 description 10
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 10
- 238000005160 1H NMR spectroscopy Methods 0.000 description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- 125000004432 carbon atom Chemical group C* 0.000 description 9
- 125000005843 halogen group Chemical group 0.000 description 9
- 238000000338 in vitro Methods 0.000 description 9
- 230000000302 ischemic effect Effects 0.000 description 9
- 230000000324 neuroprotective effect Effects 0.000 description 9
- 150000003839 salts Chemical class 0.000 description 9
- ARCGXLSVLAOJQL-UHFFFAOYSA-N trimellitic acid Chemical compound OC(=O)C1=CC=C(C(O)=O)C(C(O)=O)=C1 ARCGXLSVLAOJQL-UHFFFAOYSA-N 0.000 description 9
- LWTKTANMOKIOHE-UHFFFAOYSA-N 5-(hydroxycarbamoyl)benzene-1,3-dicarboxylic acid Chemical compound ONC(=O)C1=CC(C(O)=O)=CC(C(O)=O)=C1 LWTKTANMOKIOHE-UHFFFAOYSA-N 0.000 description 8
- 102000004190 Enzymes Human genes 0.000 description 8
- 108090000790 Enzymes Proteins 0.000 description 8
- 208000027418 Wounds and injury Diseases 0.000 description 8
- 125000003342 alkenyl group Chemical group 0.000 description 8
- 125000000217 alkyl group Chemical group 0.000 description 8
- 210000004027 cell Anatomy 0.000 description 8
- 238000004113 cell culture Methods 0.000 description 8
- 150000002430 hydrocarbons Chemical group 0.000 description 8
- 125000001424 substituent group Chemical group 0.000 description 8
- BGJFCNGRQSFWLY-UHFFFAOYSA-N 2-(carboxymethyl)terephthalic acid Chemical compound OC(=O)CC1=CC(C(O)=O)=CC=C1C(O)=O BGJFCNGRQSFWLY-UHFFFAOYSA-N 0.000 description 7
- DBWXUNFHHYACQU-UHFFFAOYSA-N 5-(3-sulfanylpropoxy)benzene-1,3-dicarboxylic acid Chemical compound OC(=O)C1=CC(OCCCS)=CC(C(O)=O)=C1 DBWXUNFHHYACQU-UHFFFAOYSA-N 0.000 description 7
- FSRPFCXLFSQONO-UHFFFAOYSA-N 5-(sulfanylmethyl)benzene-1,3-dicarboxylic acid Chemical compound OC(=O)C1=CC(CS)=CC(C(O)=O)=C1 FSRPFCXLFSQONO-UHFFFAOYSA-N 0.000 description 7
- 208000024827 Alzheimer disease Diseases 0.000 description 7
- 206010027476 Metastases Diseases 0.000 description 7
- 125000003545 alkoxy group Chemical group 0.000 description 7
- 230000002491 angiogenic effect Effects 0.000 description 7
- 238000003556 assay Methods 0.000 description 7
- 229940079593 drug Drugs 0.000 description 7
- 210000005036 nerve Anatomy 0.000 description 7
- 230000003472 neutralizing effect Effects 0.000 description 7
- 230000003287 optical effect Effects 0.000 description 7
- 208000020016 psychiatric disease Diseases 0.000 description 7
- 230000001953 sensory effect Effects 0.000 description 7
- 208000011117 substance-related disease Diseases 0.000 description 7
- 230000008733 trauma Effects 0.000 description 7
- ZRLZJJYLDWXHTG-UHFFFAOYSA-N 2-(2-carboxyphenyl)sulfanylterephthalic acid Chemical compound OC(=O)C1=CC=C(C(O)=O)C(SC=2C(=CC=CC=2)C(O)=O)=C1 ZRLZJJYLDWXHTG-UHFFFAOYSA-N 0.000 description 6
- ZZQLWVWUQYVDNC-UHFFFAOYSA-N 2-(4-carboxyphenyl)sulfonylterephthalic acid Chemical compound C1=CC(C(=O)O)=CC=C1S(=O)(=O)C1=CC(C(O)=O)=CC=C1C(O)=O ZZQLWVWUQYVDNC-UHFFFAOYSA-N 0.000 description 6
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 208000004454 Hyperalgesia Diseases 0.000 description 6
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 125000000304 alkynyl group Chemical group 0.000 description 6
- 238000009472 formulation Methods 0.000 description 6
- 230000006870 function Effects 0.000 description 6
- 229910052739 hydrogen Inorganic materials 0.000 description 6
- 239000001257 hydrogen Substances 0.000 description 6
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 6
- 230000008569 process Effects 0.000 description 6
- 230000005855 radiation Effects 0.000 description 6
- 238000001356 surgical procedure Methods 0.000 description 6
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 description 5
- XASWVQWJFORXBZ-UHFFFAOYSA-N 2-(2,5-dicarboxyphenyl)sulfonylterephthalic acid Chemical compound OC(=O)C1=CC=C(C(O)=O)C(S(=O)(=O)C=2C(=CC=C(C=2)C(O)=O)C(O)=O)=C1 XASWVQWJFORXBZ-UHFFFAOYSA-N 0.000 description 5
- MXKJSOMQCBHQQL-UHFFFAOYSA-N 4-[(1-naphthalenylamino)-oxomethyl]benzene-1,3-dicarboxylic acid Chemical compound OC(=O)C1=CC(C(=O)O)=CC=C1C(=O)NC1=CC=CC2=CC=CC=C12 MXKJSOMQCBHQQL-UHFFFAOYSA-N 0.000 description 5
- KMHCTGIQTYOFEY-UHFFFAOYSA-N 4-[3-[3-(2,4-dicarboxyphenoxy)propyldisulfanyl]propoxy]benzene-1,3-dicarboxylic acid Chemical compound OC(=O)C1=CC(C(=O)O)=CC=C1OCCCSSCCCOC1=CC=C(C(O)=O)C=C1C(O)=O KMHCTGIQTYOFEY-UHFFFAOYSA-N 0.000 description 5
- GSZXMCBCQFYVLN-UHFFFAOYSA-N 5-(2-sulfanylethoxy)benzene-1,3-dicarboxylic acid Chemical compound OC(=O)C1=CC(OCCS)=CC(C(O)=O)=C1 GSZXMCBCQFYVLN-UHFFFAOYSA-N 0.000 description 5
- AKTCPPRPHUGYMG-UHFFFAOYSA-N 5-(2-sulfanylethyl)benzene-1,3-dicarboxylic acid Chemical compound OC(=O)C1=CC(CCS)=CC(C(O)=O)=C1 AKTCPPRPHUGYMG-UHFFFAOYSA-N 0.000 description 5
- 102100041003 Glutamate carboxypeptidase 2 Human genes 0.000 description 5
- 206010039710 Scleroderma Diseases 0.000 description 5
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 5
- 210000003169 central nervous system Anatomy 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 5
- 230000001684 chronic effect Effects 0.000 description 5
- 230000001419 dependent effect Effects 0.000 description 5
- 238000011161 development Methods 0.000 description 5
- 230000018109 developmental process Effects 0.000 description 5
- 210000002683 foot Anatomy 0.000 description 5
- 238000001727 in vivo Methods 0.000 description 5
- 230000009401 metastasis Effects 0.000 description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 5
- 208000015122 neurodegenerative disease Diseases 0.000 description 5
- QUMITRDILMWWBC-UHFFFAOYSA-N nitroterephthalic acid Chemical compound OC(=O)C1=CC=C(C(O)=O)C([N+]([O-])=O)=C1 QUMITRDILMWWBC-UHFFFAOYSA-N 0.000 description 5
- QQVIHTHCMHWDBS-UHFFFAOYSA-N perisophthalic acid Natural products OC(=O)C1=CC=CC(C(O)=O)=C1 QQVIHTHCMHWDBS-UHFFFAOYSA-N 0.000 description 5
- 229940002612 prodrug Drugs 0.000 description 5
- 239000000651 prodrug Substances 0.000 description 5
- 230000004044 response Effects 0.000 description 5
- 208000011580 syndromic disease Diseases 0.000 description 5
- 238000002560 therapeutic procedure Methods 0.000 description 5
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 4
- IXODMFRJGWIMRB-UHFFFAOYSA-N 2-(carboxymethylamino)terephthalic acid Chemical compound OC(=O)CNC1=CC(C(O)=O)=CC=C1C(O)=O IXODMFRJGWIMRB-UHFFFAOYSA-N 0.000 description 4
- QBHPTQBZSVFDSO-UHFFFAOYSA-N 2-(furan-2-ylmethylamino)terephthalic acid Chemical compound OC(=O)C1=CC=C(C(O)=O)C(NCC=2OC=CC=2)=C1 QBHPTQBZSVFDSO-UHFFFAOYSA-N 0.000 description 4
- GPNNOCMCNFXRAO-UHFFFAOYSA-N 2-aminoterephthalic acid Chemical compound NC1=CC(C(O)=O)=CC=C1C(O)=O GPNNOCMCNFXRAO-UHFFFAOYSA-N 0.000 description 4
- QPBGNSFASPVGTP-UHFFFAOYSA-N 2-bromoterephthalic acid Chemical compound OC(=O)C1=CC=C(C(O)=O)C(Br)=C1 QPBGNSFASPVGTP-UHFFFAOYSA-N 0.000 description 4
- VVDOVOBSWFHMEW-UHFFFAOYSA-N 4-(2-carboxyphenyl)sulfanylbenzene-1,3-dicarboxylic acid Chemical compound OC(=O)C1=CC(C(=O)O)=CC=C1SC1=CC=CC=C1C(O)=O VVDOVOBSWFHMEW-UHFFFAOYSA-N 0.000 description 4
- YAZBUXYVODEYQE-UHFFFAOYSA-N 4-[4-(3,4-dicarboxyphenoxy)benzoyl]benzene-1,3-dicarboxylic acid Chemical compound OC(=O)C1=CC(C(=O)O)=CC=C1C(=O)C(C=C1)=CC=C1OC1=CC=C(C(O)=O)C(C(O)=O)=C1 YAZBUXYVODEYQE-UHFFFAOYSA-N 0.000 description 4
- UDBNJIRHNFFJSS-UHFFFAOYSA-N 5-(carboxymethylamino)benzene-1,3-dicarboxylic acid Chemical compound OC(=O)CNC1=CC(C(O)=O)=CC(C(O)=O)=C1 UDBNJIRHNFFJSS-UHFFFAOYSA-N 0.000 description 4
- VZEKUIOYASVZOZ-UHFFFAOYSA-N 5-[(furan-2-ylmethylamino)methyl]benzene-1,3-dicarboxylic acid Chemical compound OC(=O)C1=CC(C(=O)O)=CC(CNCC=2OC=CC=2)=C1 VZEKUIOYASVZOZ-UHFFFAOYSA-N 0.000 description 4
- HHLDJUIUOSEZSZ-UHFFFAOYSA-N 5-[2-(hydroxyamino)-2-oxoethyl]benzene-1,3-dicarboxylic acid Chemical compound ONC(=O)CC1=CC(C(O)=O)=CC(C(O)=O)=C1 HHLDJUIUOSEZSZ-UHFFFAOYSA-N 0.000 description 4
- QNVNLUSHGRBCLO-UHFFFAOYSA-N 5-hydroxybenzene-1,3-dicarboxylic acid Chemical compound OC(=O)C1=CC(O)=CC(C(O)=O)=C1 QNVNLUSHGRBCLO-UHFFFAOYSA-N 0.000 description 4
- 208000000044 Amnesia Diseases 0.000 description 4
- 208000023275 Autoimmune disease Diseases 0.000 description 4
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 description 4
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 description 4
- 125000005915 C6-C14 aryl group Chemical group 0.000 description 4
- 208000035473 Communicable disease Diseases 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 208000001613 Gambling Diseases 0.000 description 4
- 101000892862 Homo sapiens Glutamate carboxypeptidase 2 Proteins 0.000 description 4
- 208000035154 Hyperesthesia Diseases 0.000 description 4
- OTCCIMWXFLJLIA-BYPYZUCNSA-N N-acetyl-L-aspartic acid Chemical compound CC(=O)N[C@H](C(O)=O)CC(O)=O OTCCIMWXFLJLIA-BYPYZUCNSA-N 0.000 description 4
- 208000025966 Neurological disease Diseases 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 4
- 102000046299 Transforming Growth Factor beta1 Human genes 0.000 description 4
- 101800002279 Transforming growth factor beta-1 Proteins 0.000 description 4
- 241000700605 Viruses Species 0.000 description 4
- 230000006399 behavior Effects 0.000 description 4
- QMKYBPDZANOJGF-UHFFFAOYSA-N benzene-1,3,5-tricarboxylic acid Chemical compound OC(=O)C1=CC(C(O)=O)=CC(C(O)=O)=C1 QMKYBPDZANOJGF-UHFFFAOYSA-N 0.000 description 4
- KKEYFWRCBNTPAC-UHFFFAOYSA-N benzene-dicarboxylic acid Natural products OC(=O)C1=CC=C(C(O)=O)C=C1 KKEYFWRCBNTPAC-UHFFFAOYSA-N 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 210000004369 blood Anatomy 0.000 description 4
- 239000008280 blood Substances 0.000 description 4
- 230000037396 body weight Effects 0.000 description 4
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 4
- 230000010261 cell growth Effects 0.000 description 4
- 230000006735 deficit Effects 0.000 description 4
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 4
- 239000003937 drug carrier Substances 0.000 description 4
- 230000005670 electromagnetic radiation Effects 0.000 description 4
- 210000002919 epithelial cell Anatomy 0.000 description 4
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 4
- 208000027866 inflammatory disease Diseases 0.000 description 4
- 238000001802 infusion Methods 0.000 description 4
- 238000007912 intraperitoneal administration Methods 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 230000004060 metabolic process Effects 0.000 description 4
- 229910052751 metal Inorganic materials 0.000 description 4
- 239000002184 metal Substances 0.000 description 4
- 239000002858 neurotransmitter agent Substances 0.000 description 4
- 230000000144 pharmacologic effect Effects 0.000 description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 108090000765 processed proteins & peptides Proteins 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 230000009467 reduction Effects 0.000 description 4
- 230000001105 regulatory effect Effects 0.000 description 4
- 210000003497 sciatic nerve Anatomy 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 230000001988 toxicity Effects 0.000 description 4
- 231100000419 toxicity Toxicity 0.000 description 4
- HWYBBUGBCMCFAO-UHFFFAOYSA-N 4-(4-nitrobenzoyl)benzene-1,3-dicarboxylic acid Chemical compound OC(=O)C1=CC(C(=O)O)=CC=C1C(=O)C1=CC=C([N+]([O-])=O)C=C1 HWYBBUGBCMCFAO-UHFFFAOYSA-N 0.000 description 3
- YTLFYCJSQFMWSA-UHFFFAOYSA-N 4-(furan-2-ylmethylamino)benzene-1,3-dicarboxylic acid Chemical compound OC(=O)C1=CC(C(=O)O)=CC=C1NCC1=CC=CO1 YTLFYCJSQFMWSA-UHFFFAOYSA-N 0.000 description 3
- ONRMWOURASQYOP-UHFFFAOYSA-N 4-[(2,4,6-trimethylphenyl)carbamoyl]benzene-1,3-dicarboxylic acid Chemical compound CC1=CC(C)=CC(C)=C1NC(=O)C1=CC=C(C(O)=O)C=C1C(O)=O ONRMWOURASQYOP-UHFFFAOYSA-N 0.000 description 3
- BCEQKAQCUWUNML-UHFFFAOYSA-N 4-hydroxybenzene-1,3-dicarboxylic acid Chemical compound OC(=O)C1=CC=C(O)C(C(O)=O)=C1 BCEQKAQCUWUNML-UHFFFAOYSA-N 0.000 description 3
- OCJFXVHDIVAONP-UHFFFAOYSA-N 4-nitroisophthalic acid Chemical compound OC(=O)C1=CC=C([N+]([O-])=O)C(C(O)=O)=C1 OCJFXVHDIVAONP-UHFFFAOYSA-N 0.000 description 3
- MKKODOYJRMAENI-UHFFFAOYSA-N 5-(4-carboxy-2-nitrophenoxy)benzene-1,3-dicarboxylic acid Chemical compound [O-][N+](=O)C1=CC(C(=O)O)=CC=C1OC1=CC(C(O)=O)=CC(C(O)=O)=C1 MKKODOYJRMAENI-UHFFFAOYSA-N 0.000 description 3
- VFNZTYQHZZQJCW-UHFFFAOYSA-N 5-(5-methyl-3-phenyl-3,4-dihydropyrazol-2-yl)benzene-1,3-dicarboxylic acid Chemical compound C1C(C)=NN(C=2C=C(C=C(C=2)C(O)=O)C(O)=O)C1C1=CC=CC=C1 VFNZTYQHZZQJCW-UHFFFAOYSA-N 0.000 description 3
- CARJPEPCULYFFP-UHFFFAOYSA-N 5-Sulfo-1,3-benzenedicarboxylic acid Chemical compound OC(=O)C1=CC(C(O)=O)=CC(S(O)(=O)=O)=C1 CARJPEPCULYFFP-UHFFFAOYSA-N 0.000 description 3
- RHEKWZUZDKEYHJ-UHFFFAOYSA-N 5-[(carboxymethylamino)methyl]benzene-1,3-dicarboxylic acid Chemical compound OC(=O)CNCC1=CC(C(O)=O)=CC(C(O)=O)=C1 RHEKWZUZDKEYHJ-UHFFFAOYSA-N 0.000 description 3
- BOZWGYDPVUNMCN-UHFFFAOYSA-N 5-[3-(4-hydroxyphenyl)-5-phenyl-3,4-dihydropyrazol-2-yl]benzene-1,3-dicarboxylic acid Chemical compound OC(=O)C1=CC(C(=O)O)=CC(N2C(CC(=N2)C=2C=CC=CC=2)C=2C=CC(O)=CC=2)=C1 BOZWGYDPVUNMCN-UHFFFAOYSA-N 0.000 description 3
- UBNRIXQTQJPTOX-UHFFFAOYSA-N 5-[[3-(4-acetamidophenyl)-3-oxopropanoyl]amino]benzene-1,3-dicarboxylic acid Chemical compound C1=CC(NC(=O)C)=CC=C1C(=O)CC(=O)NC1=CC(C(O)=O)=CC(C(O)=O)=C1 UBNRIXQTQJPTOX-UHFFFAOYSA-N 0.000 description 3
- KQQYZSYKZQESPQ-UHFFFAOYSA-N 5-acetamidobenzene-1,3-dicarboxylic acid Chemical compound CC(=O)NC1=CC(C(O)=O)=CC(C(O)=O)=C1 KQQYZSYKZQESPQ-UHFFFAOYSA-N 0.000 description 3
- KBZFDRWPMZESDI-UHFFFAOYSA-N 5-aminobenzene-1,3-dicarboxylic acid Chemical compound NC1=CC(C(O)=O)=CC(C(O)=O)=C1 KBZFDRWPMZESDI-UHFFFAOYSA-N 0.000 description 3
- NBDAHKQJXVLAID-UHFFFAOYSA-N 5-nitroisophthalic acid Chemical compound OC(=O)C1=CC(C(O)=O)=CC([N+]([O-])=O)=C1 NBDAHKQJXVLAID-UHFFFAOYSA-N 0.000 description 3
- INJNMXHKFWFNLW-UHFFFAOYSA-N 5-phosphonobenzene-1,3-dicarboxylic acid Chemical compound OC(=O)C1=CC(C(O)=O)=CC(P(O)(O)=O)=C1 INJNMXHKFWFNLW-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- 208000036864 Attention deficit/hyperactivity disease Diseases 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- RGSFGYAAUTVSQA-UHFFFAOYSA-N Cyclopentane Chemical compound C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 description 3
- PMATZTZNYRCHOR-CGLBZJNRSA-N Cyclosporin A Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O PMATZTZNYRCHOR-CGLBZJNRSA-N 0.000 description 3
- 229930105110 Cyclosporin A Natural products 0.000 description 3
- 108010036949 Cyclosporine Proteins 0.000 description 3
- MQJKPEGWNLWLTK-UHFFFAOYSA-N Dapsone Chemical compound C1=CC(N)=CC=C1S(=O)(=O)C1=CC=C(N)C=C1 MQJKPEGWNLWLTK-UHFFFAOYSA-N 0.000 description 3
- 208000035895 Guillain-Barré syndrome Diseases 0.000 description 3
- 206010019196 Head injury Diseases 0.000 description 3
- 206010061218 Inflammation Diseases 0.000 description 3
- 208000026139 Memory disease Diseases 0.000 description 3
- 206010049567 Miller Fisher syndrome Diseases 0.000 description 3
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 3
- 229930012538 Paclitaxel Natural products 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- 229910006069 SO3H Inorganic materials 0.000 description 3
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical class [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 230000002159 abnormal effect Effects 0.000 description 3
- 230000001154 acute effect Effects 0.000 description 3
- 125000002723 alicyclic group Chemical group 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- 150000001413 amino acids Chemical group 0.000 description 3
- 125000004429 atom Chemical group 0.000 description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 210000002469 basement membrane Anatomy 0.000 description 3
- 230000004071 biological effect Effects 0.000 description 3
- 125000002837 carbocyclic group Chemical group 0.000 description 3
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 3
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 238000002512 chemotherapy Methods 0.000 description 3
- 229960001265 ciclosporin Drugs 0.000 description 3
- 239000012230 colorless oil Substances 0.000 description 3
- 230000006957 competitive inhibition Effects 0.000 description 3
- 125000004122 cyclic group Chemical group 0.000 description 3
- 229960000860 dapsone Drugs 0.000 description 3
- 230000003247 decreasing effect Effects 0.000 description 3
- 238000000921 elemental analysis Methods 0.000 description 3
- BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 description 3
- DMEGYFMYUHOHGS-UHFFFAOYSA-N heptamethylene Natural products C1CCCCCC1 DMEGYFMYUHOHGS-UHFFFAOYSA-N 0.000 description 3
- 210000000548 hind-foot Anatomy 0.000 description 3
- 238000005462 in vivo assay Methods 0.000 description 3
- 208000035231 inattentive type attention deficit hyperactivity disease Diseases 0.000 description 3
- 208000015181 infectious disease Diseases 0.000 description 3
- 230000004054 inflammatory process Effects 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 208000017169 kidney disease Diseases 0.000 description 3
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 230000006984 memory degeneration Effects 0.000 description 3
- 208000023060 memory loss Diseases 0.000 description 3
- 206010028537 myelofibrosis Diseases 0.000 description 3
- 210000000944 nerve tissue Anatomy 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 210000000056 organ Anatomy 0.000 description 3
- 229910052760 oxygen Inorganic materials 0.000 description 3
- 239000001301 oxygen Substances 0.000 description 3
- 229960001592 paclitaxel Drugs 0.000 description 3
- 230000001717 pathogenic effect Effects 0.000 description 3
- 239000002243 precursor Substances 0.000 description 3
- 210000002307 prostate Anatomy 0.000 description 3
- 230000010410 reperfusion Effects 0.000 description 3
- 230000035807 sensation Effects 0.000 description 3
- 235000019615 sensations Nutrition 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 208000020431 spinal cord injury Diseases 0.000 description 3
- 230000004936 stimulating effect Effects 0.000 description 3
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- 230000000451 tissue damage Effects 0.000 description 3
- 231100000827 tissue damage Toxicity 0.000 description 3
- 239000003053 toxin Substances 0.000 description 3
- 231100000765 toxin Toxicity 0.000 description 3
- 108700012359 toxins Proteins 0.000 description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 3
- 210000004881 tumor cell Anatomy 0.000 description 3
- 230000004614 tumor growth Effects 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 125000006700 (C1-C6) alkylthio group Chemical group 0.000 description 2
- 0 *C1=NN(C)C([Ar])C1 Chemical compound *C1=NN(C)C([Ar])C1 0.000 description 2
- NEAQRZUHTPSBBM-UHFFFAOYSA-N 2-hydroxy-3,3-dimethyl-7-nitro-4h-isoquinolin-1-one Chemical class C1=C([N+]([O-])=O)C=C2C(=O)N(O)C(C)(C)CC2=C1 NEAQRZUHTPSBBM-UHFFFAOYSA-N 0.000 description 2
- 208000030507 AIDS Diseases 0.000 description 2
- 208000007122 AIDS-Associated Nephropathy Diseases 0.000 description 2
- 206010004664 Biliary fibrosis Diseases 0.000 description 2
- 208000003174 Brain Neoplasms Diseases 0.000 description 2
- 125000003320 C2-C6 alkenyloxy group Chemical group 0.000 description 2
- 239000004215 Carbon black (E152) Substances 0.000 description 2
- 208000024172 Cardiovascular disease Diseases 0.000 description 2
- 208000029147 Collagen-vascular disease Diseases 0.000 description 2
- 206010012335 Dependence Diseases 0.000 description 2
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 2
- 208000007342 Diabetic Nephropathies Diseases 0.000 description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 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
- 208000030814 Eating disease Diseases 0.000 description 2
- 102000010834 Extracellular Matrix Proteins Human genes 0.000 description 2
- 108010037362 Extracellular Matrix Proteins Proteins 0.000 description 2
- 206010016228 Fasciitis Diseases 0.000 description 2
- 208000019454 Feeding and Eating disease Diseases 0.000 description 2
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 2
- 206010018378 Glomerulonephritis rapidly progressive Diseases 0.000 description 2
- 206010070737 HIV associated nephropathy Diseases 0.000 description 2
- 208000032843 Hemorrhage Diseases 0.000 description 2
- 208000023105 Huntington disease Diseases 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- 206010062016 Immunosuppression Diseases 0.000 description 2
- 208000029523 Interstitial Lung disease Diseases 0.000 description 2
- 206010023421 Kidney fibrosis Diseases 0.000 description 2
- 208000000185 Localized scleroderma Diseases 0.000 description 2
- 108010010914 Metabotropic glutamate receptors Proteins 0.000 description 2
- 102000016193 Metabotropic glutamate receptors Human genes 0.000 description 2
- 206010027982 Morphoea Diseases 0.000 description 2
- OTCCIMWXFLJLIA-UHFFFAOYSA-N N-acetyl-DL-aspartic acid Natural products CC(=O)NC(C(O)=O)CC(O)=O OTCCIMWXFLJLIA-UHFFFAOYSA-N 0.000 description 2
- 208000008589 Obesity Diseases 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- 206010034158 Pathological gambling Diseases 0.000 description 2
- 102000035195 Peptidases Human genes 0.000 description 2
- 108091005804 Peptidases Proteins 0.000 description 2
- 208000018262 Peripheral vascular disease Diseases 0.000 description 2
- 206010034912 Phobia Diseases 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- 241000097929 Porphyria Species 0.000 description 2
- 208000010642 Porphyrias Diseases 0.000 description 2
- 206010036376 Postherpetic Neuralgia Diseases 0.000 description 2
- 208000002158 Proliferative Vitreoretinopathy Diseases 0.000 description 2
- 208000003782 Raynaud disease Diseases 0.000 description 2
- 208000012322 Raynaud phenomenon Diseases 0.000 description 2
- 206010038934 Retinopathy proliferative Diseases 0.000 description 2
- 241000606701 Rickettsia Species 0.000 description 2
- 206010039705 Scleritis Diseases 0.000 description 2
- 206010039966 Senile dementia Diseases 0.000 description 2
- BLRPTPMANUNPDV-UHFFFAOYSA-N Silane Chemical group [SiH4] BLRPTPMANUNPDV-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 208000007271 Substance Withdrawal Syndrome Diseases 0.000 description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 2
- 208000000323 Tourette Syndrome Diseases 0.000 description 2
- 208000016620 Tourette disease Diseases 0.000 description 2
- 241000223996 Toxoplasma Species 0.000 description 2
- 102000011117 Transforming Growth Factor beta2 Human genes 0.000 description 2
- 101800000304 Transforming growth factor beta-2 Proteins 0.000 description 2
- 208000025865 Ulcer Diseases 0.000 description 2
- 206010052428 Wound Diseases 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 239000002671 adjuvant Substances 0.000 description 2
- 229940024606 amino acid Drugs 0.000 description 2
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 description 2
- 206010002022 amyloidosis Diseases 0.000 description 2
- MWPLVEDNUUSJAV-UHFFFAOYSA-N anthracene Chemical compound C1=CC=CC2=CC3=CC=CC=C3C=C21 MWPLVEDNUUSJAV-UHFFFAOYSA-N 0.000 description 2
- 125000002178 anthracenyl group Chemical group C1(=CC=CC2=CC3=CC=CC=C3C=C12)* 0.000 description 2
- 206010003074 arachnoiditis Diseases 0.000 description 2
- 125000002648 azanetriyl group Chemical group *N(*)* 0.000 description 2
- 230000003542 behavioural effect Effects 0.000 description 2
- 239000004305 biphenyl Substances 0.000 description 2
- 235000010290 biphenyl Nutrition 0.000 description 2
- 230000008499 blood brain barrier function Effects 0.000 description 2
- 230000017531 blood circulation Effects 0.000 description 2
- 210000001218 blood-brain barrier Anatomy 0.000 description 2
- 150000001649 bromium compounds Chemical class 0.000 description 2
- 125000001246 bromo group Chemical group Br* 0.000 description 2
- 239000006172 buffering agent Substances 0.000 description 2
- 230000009400 cancer invasion Effects 0.000 description 2
- 125000001309 chloro group Chemical group Cl* 0.000 description 2
- 125000002378 chlorosyl group Chemical group O=Cl[*] 0.000 description 2
- 229910001916 chloryl Inorganic materials 0.000 description 2
- 125000000622 chloryl group Chemical group O=Cl(=O)[*] 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 208000019425 cirrhosis of liver Diseases 0.000 description 2
- 238000011260 co-administration Methods 0.000 description 2
- ZPUCINDJVBIVPJ-LJISPDSOSA-N cocaine Chemical compound O([C@H]1C[C@@H]2CC[C@@H](N2C)[C@H]1C(=O)OC)C(=O)C1=CC=CC=C1 ZPUCINDJVBIVPJ-LJISPDSOSA-N 0.000 description 2
- 230000006835 compression Effects 0.000 description 2
- 238000007906 compression Methods 0.000 description 2
- 208000018631 connective tissue disease Diseases 0.000 description 2
- 201000005637 crescentic glomerulonephritis Diseases 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- HGCIXCUEYOPUTN-UHFFFAOYSA-N cyclohexene Chemical compound C1CCC=CC1 HGCIXCUEYOPUTN-UHFFFAOYSA-N 0.000 description 2
- LPIQUOYDBNQMRZ-UHFFFAOYSA-N cyclopentene Chemical compound C1CC=CC1 LPIQUOYDBNQMRZ-UHFFFAOYSA-N 0.000 description 2
- 229930182912 cyclosporin Natural products 0.000 description 2
- 230000007812 deficiency Effects 0.000 description 2
- 201000001981 dermatomyositis Diseases 0.000 description 2
- 208000033679 diabetic kidney disease Diseases 0.000 description 2
- 235000005911 diet Nutrition 0.000 description 2
- 230000037213 diet Effects 0.000 description 2
- VXLVIZXUPLOKQG-UHFFFAOYSA-N diethyl 5-(diethoxyphosphorylmethyl)benzene-1,3-dicarboxylate Chemical compound CCOC(=O)C1=CC(CP(=O)(OCC)OCC)=CC(C(=O)OCC)=C1 VXLVIZXUPLOKQG-UHFFFAOYSA-N 0.000 description 2
- RTMDFQZSKXWWKT-UHFFFAOYSA-N diethyl 5-(hydroxycarbamoyl)benzene-1,3-dicarboxylate Chemical compound CCOC(=O)C1=CC(C(=O)NO)=CC(C(=O)OCC)=C1 RTMDFQZSKXWWKT-UHFFFAOYSA-N 0.000 description 2
- HMRCTBKXKNDMFF-UHFFFAOYSA-N diethyl 5-(phenylmethoxycarbamoyl)benzene-1,3-dicarboxylate Chemical compound CCOC(=O)C1=CC(C(=O)OCC)=CC(C(=O)NOCC=2C=CC=CC=2)=C1 HMRCTBKXKNDMFF-UHFFFAOYSA-N 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- KYYSKSSAKAILMM-UHFFFAOYSA-N dimethyl 4-(2-acetylsulfanylethyl)benzene-1,3-dicarboxylate Chemical compound COC(=O)C1=CC=C(CCSC(C)=O)C(C(=O)OC)=C1 KYYSKSSAKAILMM-UHFFFAOYSA-N 0.000 description 2
- SIAYIRJZJUTZNI-UHFFFAOYSA-N dimethyl 4-(trifluoromethylsulfonyloxy)benzene-1,3-dicarboxylate Chemical compound COC(=O)C1=CC=C(OS(=O)(=O)C(F)(F)F)C(C(=O)OC)=C1 SIAYIRJZJUTZNI-UHFFFAOYSA-N 0.000 description 2
- ITRRZWKQFLJRMX-UHFFFAOYSA-N dimethyl 4-ethenylbenzene-1,3-dicarboxylate Chemical compound COC(=O)C1=CC=C(C=C)C(C(=O)OC)=C1 ITRRZWKQFLJRMX-UHFFFAOYSA-N 0.000 description 2
- 230000003292 diminished effect Effects 0.000 description 2
- 125000000104 diselanyl group Chemical group [*][Se][Se][H] 0.000 description 2
- 235000014632 disordered eating Nutrition 0.000 description 2
- 230000009429 distress Effects 0.000 description 2
- 239000003995 emulsifying agent Substances 0.000 description 2
- 210000002889 endothelial cell Anatomy 0.000 description 2
- 230000002327 eosinophilic effect Effects 0.000 description 2
- 206010015037 epilepsy Diseases 0.000 description 2
- 210000000981 epithelium Anatomy 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 230000001747 exhibiting effect Effects 0.000 description 2
- 210000002744 extracellular matrix Anatomy 0.000 description 2
- 230000000893 fibroproliferative effect Effects 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- 125000002541 furyl group Chemical group 0.000 description 2
- 229960003692 gamma aminobutyric acid Drugs 0.000 description 2
- 239000003102 growth factor Substances 0.000 description 2
- 201000009277 hairy cell leukemia Diseases 0.000 description 2
- 125000001188 haloalkyl group Chemical group 0.000 description 2
- 125000001475 halogen functional group Chemical group 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- 125000005842 heteroatom Chemical group 0.000 description 2
- 229930195733 hydrocarbon Natural products 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 208000013403 hyperactivity Diseases 0.000 description 2
- 230000000917 hyperalgesic effect Effects 0.000 description 2
- 125000001841 imino group Chemical group [H]N=* 0.000 description 2
- 230000036737 immune function Effects 0.000 description 2
- 230000001506 immunosuppresive effect Effects 0.000 description 2
- 230000000977 initiatory effect Effects 0.000 description 2
- 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 2
- 230000035987 intoxication Effects 0.000 description 2
- 231100000566 intoxication Toxicity 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 238000007914 intraventricular administration Methods 0.000 description 2
- 150000004694 iodide salts Chemical class 0.000 description 2
- 125000001812 iodosyl group Chemical group O=I[*] 0.000 description 2
- 125000002512 iodyl group Chemical group O=I(=O)[*] 0.000 description 2
- 108010076560 isospaglumic acid Proteins 0.000 description 2
- CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 2
- 210000002540 macrophage Anatomy 0.000 description 2
- 230000014759 maintenance of location Effects 0.000 description 2
- 230000010534 mechanism of action Effects 0.000 description 2
- 230000001404 mediated effect Effects 0.000 description 2
- 201000008265 mesangial proliferative glomerulonephritis Diseases 0.000 description 2
- RHCSKNNOAZULRK-UHFFFAOYSA-N mescaline Chemical compound COC1=CC(CCN)=CC(OC)=C1OC RHCSKNNOAZULRK-UHFFFAOYSA-N 0.000 description 2
- 230000002503 metabolic effect Effects 0.000 description 2
- 239000002207 metabolite Substances 0.000 description 2
- 206010061289 metastatic neoplasm Diseases 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 208000001022 morbid obesity Diseases 0.000 description 2
- 210000003205 muscle Anatomy 0.000 description 2
- 230000023105 myelination Effects 0.000 description 2
- 125000001624 naphthyl group Chemical group 0.000 description 2
- 208000021971 neovascular inflammatory vitreoretinopathy Diseases 0.000 description 2
- 210000004498 neuroglial cell Anatomy 0.000 description 2
- 230000003961 neuronal insult Effects 0.000 description 2
- 230000004112 neuroprotection Effects 0.000 description 2
- 125000000018 nitroso group Chemical group N(=O)* 0.000 description 2
- 230000006959 non-competitive inhibition Effects 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- 235000020824 obesity Nutrition 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 2
- 208000019906 panic disease Diseases 0.000 description 2
- 244000052769 pathogen Species 0.000 description 2
- 229910001917 perchloryl Inorganic materials 0.000 description 2
- 125000002322 perchloryl group Chemical group *Cl(=O)(=O)=O 0.000 description 2
- 210000001428 peripheral nervous system Anatomy 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 230000000704 physical effect Effects 0.000 description 2
- 201000000317 pneumocystosis Diseases 0.000 description 2
- 229920001481 poly(stearyl methacrylate) Polymers 0.000 description 2
- 208000005987 polymyositis Diseases 0.000 description 2
- 230000001242 postsynaptic effect Effects 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 102000004196 processed proteins & peptides Human genes 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 230000000750 progressive effect Effects 0.000 description 2
- 230000006785 proliferative vitreoretinopathy Effects 0.000 description 2
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 235000019833 protease Nutrition 0.000 description 2
- BBEAQIROQSPTKN-UHFFFAOYSA-N pyrene Chemical compound C1=CC=C2C=CC3=CC=CC4=CC=C1C2=C43 BBEAQIROQSPTKN-UHFFFAOYSA-N 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 125000004076 pyridyl group Chemical group 0.000 description 2
- 125000000714 pyrimidinyl group Chemical group 0.000 description 2
- 230000002829 reductive effect Effects 0.000 description 2
- 201000002793 renal fibrosis Diseases 0.000 description 2
- 239000011347 resin Substances 0.000 description 2
- 229920005989 resin Polymers 0.000 description 2
- 206010039073 rheumatoid arthritis Diseases 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 229930195734 saturated hydrocarbon Natural products 0.000 description 2
- 230000035945 sensitivity Effects 0.000 description 2
- 230000020341 sensory perception of pain Effects 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 125000004469 siloxy group Chemical group [SiH3]O* 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 201000001716 specific phobia Diseases 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 201000009032 substance abuse Diseases 0.000 description 2
- 201000006152 substance dependence Diseases 0.000 description 2
- 235000000346 sugar Nutrition 0.000 description 2
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 description 2
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 2
- 229910052717 sulfur Inorganic materials 0.000 description 2
- 239000011593 sulfur Substances 0.000 description 2
- 230000000946 synaptic effect Effects 0.000 description 2
- 208000006379 syphilis Diseases 0.000 description 2
- 201000000596 systemic lupus erythematosus Diseases 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 150000003536 tetrazoles Chemical class 0.000 description 2
- 229940124597 therapeutic agent Drugs 0.000 description 2
- 125000001544 thienyl group Chemical group 0.000 description 2
- 125000003396 thiol group Chemical group [H]S* 0.000 description 2
- 229930192474 thiophene Natural products 0.000 description 2
- 230000009772 tissue formation Effects 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 230000001052 transient effect Effects 0.000 description 2
- WJKHJLXJJJATHN-UHFFFAOYSA-N triflic anhydride Chemical compound FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F WJKHJLXJJJATHN-UHFFFAOYSA-N 0.000 description 2
- 231100000397 ulcer Toxicity 0.000 description 2
- 230000006967 uncompetitive inhibition Effects 0.000 description 2
- 210000002700 urine Anatomy 0.000 description 2
- 229960005486 vaccine Drugs 0.000 description 2
- 239000000080 wetting agent Substances 0.000 description 2
- LSPHULWDVZXLIL-UHFFFAOYSA-N (+/-)-Camphoric acid Chemical compound CC1(C)C(C(O)=O)CCC1(C)C(O)=O LSPHULWDVZXLIL-UHFFFAOYSA-N 0.000 description 1
- OGNSCSPNOLGXSM-UHFFFAOYSA-N (+/-)-DABA Natural products NCCC(N)C(O)=O OGNSCSPNOLGXSM-UHFFFAOYSA-N 0.000 description 1
- SNICXCGAKADSCV-JTQLQIEISA-N (-)-Nicotine Chemical compound CN1CCC[C@H]1C1=CC=CN=C1 SNICXCGAKADSCV-JTQLQIEISA-N 0.000 description 1
- ASGMFNBUXDJWJJ-JLCFBVMHSA-N (1R,3R)-3-[[3-bromo-1-[4-(5-methyl-1,3,4-thiadiazol-2-yl)phenyl]pyrazolo[3,4-d]pyrimidin-6-yl]amino]-N,1-dimethylcyclopentane-1-carboxamide Chemical compound BrC1=NN(C2=NC(=NC=C21)N[C@H]1C[C@@](CC1)(C(=O)NC)C)C1=CC=C(C=C1)C=1SC(=NN=1)C ASGMFNBUXDJWJJ-JLCFBVMHSA-N 0.000 description 1
- WWTBZEKOSBFBEM-SPWPXUSOSA-N (2s)-2-[[2-benzyl-3-[hydroxy-[(1r)-2-phenyl-1-(phenylmethoxycarbonylamino)ethyl]phosphoryl]propanoyl]amino]-3-(1h-indol-3-yl)propanoic acid Chemical compound N([C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)O)C(=O)C(CP(O)(=O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1C=CC=CC=1)CC1=CC=CC=C1 WWTBZEKOSBFBEM-SPWPXUSOSA-N 0.000 description 1
- HUWSZNZAROKDRZ-RRLWZMAJSA-N (3r,4r)-3-azaniumyl-5-[[(2s,3r)-1-[(2s)-2,3-dicarboxypyrrolidin-1-yl]-3-methyl-1-oxopentan-2-yl]amino]-5-oxo-4-sulfanylpentane-1-sulfonate Chemical compound OS(=O)(=O)CC[C@@H](N)[C@@H](S)C(=O)N[C@@H]([C@H](C)CC)C(=O)N1CCC(C(O)=O)[C@H]1C(O)=O HUWSZNZAROKDRZ-RRLWZMAJSA-N 0.000 description 1
- VRYALKFFQXWPIH-PBXRRBTRSA-N (3r,4s,5r)-3,4,5,6-tetrahydroxyhexanal Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)CC=O VRYALKFFQXWPIH-PBXRRBTRSA-N 0.000 description 1
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 description 1
- KWTSXDURSIMDCE-QMMMGPOBSA-N (S)-amphetamine Chemical compound C[C@H](N)CC1=CC=CC=C1 KWTSXDURSIMDCE-QMMMGPOBSA-N 0.000 description 1
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 description 1
- ZEHYJZXQEQOSON-AATRIKPKSA-N (e)-1-chloro-3-ethylpent-1-en-4-yn-3-ol Chemical compound CCC(O)(C#C)\C=C\Cl ZEHYJZXQEQOSON-AATRIKPKSA-N 0.000 description 1
- CIISBYKBBMFLEZ-UHFFFAOYSA-N 1,2-oxazolidine Chemical compound C1CNOC1 CIISBYKBBMFLEZ-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- VFWCMGCRMGJXDK-UHFFFAOYSA-N 1-chlorobutane Chemical class CCCCCl VFWCMGCRMGJXDK-UHFFFAOYSA-N 0.000 description 1
- VUQPJRPDRDVQMN-UHFFFAOYSA-N 1-chlorooctadecane Chemical class CCCCCCCCCCCCCCCCCCCl VUQPJRPDRDVQMN-UHFFFAOYSA-N 0.000 description 1
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- YBYIRNPNPLQARY-UHFFFAOYSA-N 1H-indene Natural products C1=CC=C2CC=CC2=C1 YBYIRNPNPLQARY-UHFFFAOYSA-N 0.000 description 1
- KJUGUADJHNHALS-UHFFFAOYSA-N 1H-tetrazole Substances C=1N=NNN=1 KJUGUADJHNHALS-UHFFFAOYSA-N 0.000 description 1
- CARFETJZUQORNQ-UHFFFAOYSA-N 1h-pyrrole-2-thiol Chemical class SC1=CC=CN1 CARFETJZUQORNQ-UHFFFAOYSA-N 0.000 description 1
- WIZIBEDAPVILNL-UHFFFAOYSA-N 1h-pyrrolo[2,3-b]pyridine-2,3-dione Chemical compound C1=CC=C2C(=O)C(=O)NC2=N1 WIZIBEDAPVILNL-UHFFFAOYSA-N 0.000 description 1
- OZAIFHULBGXAKX-UHFFFAOYSA-N 2-(2-cyanopropan-2-yldiazenyl)-2-methylpropanenitrile Chemical compound N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 description 1
- SMGZBRVSYVJHCB-UHFFFAOYSA-N 2-(2-sulfanylethyl)pentanedioic acid Chemical compound OC(=O)CCC(C(O)=O)CCS SMGZBRVSYVJHCB-UHFFFAOYSA-N 0.000 description 1
- FNLNSQHJKVQCBP-UHFFFAOYSA-N 2-(3-sulfanylpropyl)pentanedioic acid Chemical compound OC(=O)CCC(C(O)=O)CCCS FNLNSQHJKVQCBP-UHFFFAOYSA-N 0.000 description 1
- ISEYJGQFXSTPMQ-UHFFFAOYSA-N 2-(phosphonomethyl)pentanedioic acid Chemical compound OC(=O)CCC(C(O)=O)CP(O)(O)=O ISEYJGQFXSTPMQ-UHFFFAOYSA-N 0.000 description 1
- SVAHMQCUSNJPRX-UHFFFAOYSA-N 2-[[hydroxy-[(2,3,4,5,6-pentafluorophenyl)methyl]phosphoryl]methyl]pentanedioic acid Chemical compound OC(=O)CCC(C(O)=O)CP(O)(=O)CC1=C(F)C(F)=C(F)C(F)=C1F SVAHMQCUSNJPRX-UHFFFAOYSA-N 0.000 description 1
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 1
- 229940080296 2-naphthalenesulfonate Drugs 0.000 description 1
- WMPPDTMATNBGJN-UHFFFAOYSA-N 2-phenylethylbromide Chemical class BrCCC1=CC=CC=C1 WMPPDTMATNBGJN-UHFFFAOYSA-N 0.000 description 1
- ADWMKGCKKNULPN-UHFFFAOYSA-N 2-sulfinylpyrrole Chemical class O=S=C1C=CC=N1 ADWMKGCKKNULPN-UHFFFAOYSA-N 0.000 description 1
- JRZBWRPPYOMOJE-UHFFFAOYSA-N 2-sulfonylpyrrole Chemical class O=S(=O)=C1C=CC=N1 JRZBWRPPYOMOJE-UHFFFAOYSA-N 0.000 description 1
- RAADBCJYJHQQBI-UHFFFAOYSA-N 2-sulfoterephthalic acid Chemical compound OC(=O)C1=CC=C(C(O)=O)C(S(O)(=O)=O)=C1 RAADBCJYJHQQBI-UHFFFAOYSA-N 0.000 description 1
- ZRPLANDPDWYOMZ-UHFFFAOYSA-N 3-cyclopentylpropionic acid Chemical compound OC(=O)CCC1CCCC1 ZRPLANDPDWYOMZ-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- YURYXANPFWEPEI-UHFFFAOYSA-N 5-(bromomethyl)benzene-1,3-dicarboxylic acid Chemical compound OC(=O)C1=CC(CBr)=CC(C(O)=O)=C1 YURYXANPFWEPEI-UHFFFAOYSA-N 0.000 description 1
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 description 1
- OZAIFHULBGXAKX-VAWYXSNFSA-N AIBN Substances N#CC(C)(C)\N=N\C(C)(C)C#N OZAIFHULBGXAKX-VAWYXSNFSA-N 0.000 description 1
- 206010000050 Abdominal adhesions Diseases 0.000 description 1
- 208000012260 Accidental injury Diseases 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 208000024893 Acute lymphoblastic leukemia Diseases 0.000 description 1
- 208000014697 Acute lymphocytic leukaemia Diseases 0.000 description 1
- 208000031261 Acute myeloid leukaemia Diseases 0.000 description 1
- 206010001052 Acute respiratory distress syndrome Diseases 0.000 description 1
- 208000006468 Adrenal Cortex Neoplasms Diseases 0.000 description 1
- 208000008811 Agoraphobia Diseases 0.000 description 1
- 208000035285 Allergic Seasonal Rhinitis Diseases 0.000 description 1
- 206010001935 American trypanosomiasis Diseases 0.000 description 1
- 206010059199 Anterior chamber cleavage syndrome Diseases 0.000 description 1
- 206010002859 Anxiety disorder due to a general medical condition Diseases 0.000 description 1
- 206010002945 Aphakia Diseases 0.000 description 1
- 101001044245 Arabidopsis thaliana Insulin-degrading enzyme-like 1, peroxisomal Proteins 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- 208000006096 Attention Deficit Disorder with Hyperactivity Diseases 0.000 description 1
- 208000010059 Axenfeld-Rieger syndrome Diseases 0.000 description 1
- 208000010839 B-cell chronic lymphocytic leukemia Diseases 0.000 description 1
- 239000005528 B01AC05 - Ticlopidine Substances 0.000 description 1
- 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 description 1
- 208000008035 Back Pain Diseases 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 208000006373 Bell palsy Diseases 0.000 description 1
- 206010004446 Benign prostatic hyperplasia Diseases 0.000 description 1
- 206010005003 Bladder cancer Diseases 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 208000002381 Brain Hypoxia Diseases 0.000 description 1
- 201000006474 Brain Ischemia Diseases 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- FERIUCNNQQJTOY-UHFFFAOYSA-M Butyrate Chemical compound CCCC([O-])=O FERIUCNNQQJTOY-UHFFFAOYSA-M 0.000 description 1
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Natural products CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 1
- AZXHPEMDMYAYBV-UHFFFAOYSA-M C.C.C=CC1=CC=C(C(=O)OC)C=C1C(=O)OC.C=C[Sn](CCCC)(CCCC)CCCC.CC(=O)S.CCN(CC)CC.COC(=O)C1=CC=C(CCSC(C)=O)C(C(=O)OC)=C1.COC(=O)C1=CC=C(O)C(C(=O)OC)=C1.COC(=O)C1=CC=C(OS(=O)(=O)C(F)(F)F)C(C(=O)OC)=C1.O=C(O)C1=CC=C(CCS)C(C(=O)O)=C1.O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F.OC1CCCO1.O[Na] Chemical compound C.C.C=CC1=CC=C(C(=O)OC)C=C1C(=O)OC.C=C[Sn](CCCC)(CCCC)CCCC.CC(=O)S.CCN(CC)CC.COC(=O)C1=CC=C(CCSC(C)=O)C(C(=O)OC)=C1.COC(=O)C1=CC=C(O)C(C(=O)OC)=C1.COC(=O)C1=CC=C(OS(=O)(=O)C(F)(F)F)C(C(=O)OC)=C1.O=C(O)C1=CC=C(CCS)C(C(=O)O)=C1.O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F.OC1CCCO1.O[Na] AZXHPEMDMYAYBV-UHFFFAOYSA-M 0.000 description 1
- CNUMSBJSBYZQMP-UHFFFAOYSA-M C.CCO.CCOC(=O)C1=CC(C(=O)NO)=CC(C(=O)OCC)=C1.CCOC(=O)C1=CC(C(=O)NOCC2=CC=CC=C2)=CC(C(=O)OCC)=C1.CCOC(=O)C1=CC(C(=O)O)=CC(C(=O)OCC)=C1.ClCCl.O=C(O)C1=CC(C(=O)O)=CC(C(=O)NO)=C1.O[Na] Chemical compound C.CCO.CCOC(=O)C1=CC(C(=O)NO)=CC(C(=O)OCC)=C1.CCOC(=O)C1=CC(C(=O)NOCC2=CC=CC=C2)=CC(C(=O)OCC)=C1.CCOC(=O)C1=CC(C(=O)O)=CC(C(=O)OCC)=C1.ClCCl.O=C(O)C1=CC(C(=O)O)=CC(C(=O)NO)=C1.O[Na] CNUMSBJSBYZQMP-UHFFFAOYSA-M 0.000 description 1
- PMZBHPUNQNKBOA-UHFFFAOYSA-N CC1=CC(C(=O)O)=CC(C(=O)O)=C1 Chemical compound CC1=CC(C(=O)O)=CC(C(=O)O)=C1 PMZBHPUNQNKBOA-UHFFFAOYSA-N 0.000 description 1
- UFMBOFGKHIXOTA-UHFFFAOYSA-N CC1=CC(C(=O)O)=CC=C1C(=O)O Chemical compound CC1=CC(C(=O)O)=CC=C1C(=O)O UFMBOFGKHIXOTA-UHFFFAOYSA-N 0.000 description 1
- PNWSHHILERSSLF-UHFFFAOYSA-N CC1=CC=C(C(=O)O)C=C1C(=O)O Chemical compound CC1=CC=C(C(=O)O)C=C1C(=O)O PNWSHHILERSSLF-UHFFFAOYSA-N 0.000 description 1
- DGYWQDZBRBLJOS-UHFFFAOYSA-N CCOC(=O)C1=CC(CBr)=CC(C(=O)OCC)=C1.CCOC(=O)C1=CC(CP(=O)(OCC)OCC)=CC(C(=O)OCC)=C1.O=C(O)C1=CC(CP(=O)(O)O)=CC(C(=O)O)=C1 Chemical compound CCOC(=O)C1=CC(CBr)=CC(C(=O)OCC)=C1.CCOC(=O)C1=CC(CP(=O)(OCC)OCC)=CC(C(=O)OCC)=C1.O=C(O)C1=CC(CP(=O)(O)O)=CC(C(=O)O)=C1 DGYWQDZBRBLJOS-UHFFFAOYSA-N 0.000 description 1
- WBVUOXHVUOGOLI-UHFFFAOYSA-N CN(C(=O)C1=C(O)C2=CC=CC=C2C=C1)C1=CC(C(=O)O)=CC(C(=O)O)=C1 Chemical compound CN(C(=O)C1=C(O)C2=CC=CC=C2C=C1)C1=CC(C(=O)O)=CC(C(=O)O)=C1 WBVUOXHVUOGOLI-UHFFFAOYSA-N 0.000 description 1
- PXJWKZYGUFZZRN-UHFFFAOYSA-N COC1=CC=CC=C1C(=O)CC(=O)NC1=CC(NS(=O)(=O)C2=CC(C(=O)O)=CC(C(=O)O)=C2)=CC=C1Cl Chemical compound COC1=CC=CC=C1C(=O)CC(=O)NC1=CC(NS(=O)(=O)C2=CC(C(=O)O)=CC(C(=O)O)=C2)=CC=C1Cl PXJWKZYGUFZZRN-UHFFFAOYSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 241000222122 Candida albicans Species 0.000 description 1
- 241000222173 Candida parapsilosis Species 0.000 description 1
- 241000282465 Canis Species 0.000 description 1
- 244000025254 Cannabis sativa Species 0.000 description 1
- 235000012766 Cannabis sativa ssp. sativa var. sativa Nutrition 0.000 description 1
- 235000012765 Cannabis sativa ssp. sativa var. spontanea Nutrition 0.000 description 1
- 208000001408 Carbon monoxide poisoning Diseases 0.000 description 1
- 201000009030 Carcinoma Diseases 0.000 description 1
- 206010008089 Cerebral artery occlusion Diseases 0.000 description 1
- 206010008190 Cerebrovascular accident Diseases 0.000 description 1
- 208000024699 Chagas disease Diseases 0.000 description 1
- 208000010693 Charcot-Marie-Tooth Disease Diseases 0.000 description 1
- 208000010833 Chronic myeloid leukaemia Diseases 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 229910021580 Cobalt(II) chloride Inorganic materials 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 1
- 229940127007 Compound 39 Drugs 0.000 description 1
- 206010010297 Confabulation Diseases 0.000 description 1
- 206010010356 Congenital anomaly Diseases 0.000 description 1
- 239000000055 Corticotropin-Releasing Hormone Substances 0.000 description 1
- 208000020406 Creutzfeldt Jacob disease Diseases 0.000 description 1
- 208000003407 Creutzfeldt-Jakob Syndrome Diseases 0.000 description 1
- 208000010859 Creutzfeldt-Jakob disease Diseases 0.000 description 1
- 201000007336 Cryptococcosis Diseases 0.000 description 1
- 241000221204 Cryptococcus neoformans Species 0.000 description 1
- 208000008953 Cryptosporidiosis Diseases 0.000 description 1
- 206010011502 Cryptosporidiosis infection Diseases 0.000 description 1
- PMPVIKIVABFJJI-UHFFFAOYSA-N Cyclobutane Chemical compound C1CCC1 PMPVIKIVABFJJI-UHFFFAOYSA-N 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 1
- LVZWSLJZHVFIQJ-UHFFFAOYSA-N Cyclopropane Chemical compound C1CC1 LVZWSLJZHVFIQJ-UHFFFAOYSA-N 0.000 description 1
- IGXWBGJHJZYPQS-SSDOTTSWSA-N D-Luciferin Chemical compound OC(=O)[C@H]1CSC(C=2SC3=CC=C(O)C=C3N=2)=N1 IGXWBGJHJZYPQS-SSDOTTSWSA-N 0.000 description 1
- MNQZXJOMYWMBOU-VKHMYHEASA-N D-glyceraldehyde Chemical compound OC[C@@H](O)C=O MNQZXJOMYWMBOU-VKHMYHEASA-N 0.000 description 1
- CYCGRDQQIOGCKX-UHFFFAOYSA-N Dehydro-luciferin Natural products OC(=O)C1=CSC(C=2SC3=CC(O)=CC=C3N=2)=N1 CYCGRDQQIOGCKX-UHFFFAOYSA-N 0.000 description 1
- 206010012239 Delusion Diseases 0.000 description 1
- 206010012289 Dementia Diseases 0.000 description 1
- 206010012305 Demyelination Diseases 0.000 description 1
- 206010012565 Developmental glaucoma Diseases 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 206010012645 Diabetic autonomic neuropathy Diseases 0.000 description 1
- 206010012676 Diabetic mononeuropathy Diseases 0.000 description 1
- XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical class C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 description 1
- 201000003066 Diffuse Scleroderma Diseases 0.000 description 1
- 208000035240 Disease Resistance Diseases 0.000 description 1
- 208000012661 Dyskinesia Diseases 0.000 description 1
- 206010014733 Endometrial cancer Diseases 0.000 description 1
- 206010014759 Endometrial neoplasm Diseases 0.000 description 1
- 206010015084 Episcleritis Diseases 0.000 description 1
- 241000283073 Equus caballus Species 0.000 description 1
- 208000000461 Esophageal Neoplasms Diseases 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- 208000006168 Ewing Sarcoma Diseases 0.000 description 1
- 206010015866 Extravasation Diseases 0.000 description 1
- 241000282324 Felis Species 0.000 description 1
- BJGNCJDXODQBOB-UHFFFAOYSA-N Fivefly Luciferin Natural products OC(=O)C1CSC(C=2SC3=CC(O)=CC=C3N=2)=N1 BJGNCJDXODQBOB-UHFFFAOYSA-N 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- 241000233866 Fungi Species 0.000 description 1
- 208000022072 Gallbladder Neoplasms Diseases 0.000 description 1
- 206010064571 Gene mutation Diseases 0.000 description 1
- 208000011688 Generalised anxiety disease Diseases 0.000 description 1
- 208000021965 Glossopharyngeal Nerve disease Diseases 0.000 description 1
- 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 1
- 108010027915 Glutamate Receptors Proteins 0.000 description 1
- 102000018899 Glutamate Receptors Human genes 0.000 description 1
- 229940122459 Glutamate antagonist Drugs 0.000 description 1
- JMBQKKAJIKAWKF-UHFFFAOYSA-N Glutethimide Chemical compound C=1C=CC=CC=1C1(CC)CCC(=O)NC1=O JMBQKKAJIKAWKF-UHFFFAOYSA-N 0.000 description 1
- 208000004547 Hallucinations Diseases 0.000 description 1
- 208000010496 Heart Arrest Diseases 0.000 description 1
- 241000228404 Histoplasma capsulatum Species 0.000 description 1
- 208000017604 Hodgkin disease Diseases 0.000 description 1
- 208000021519 Hodgkin lymphoma Diseases 0.000 description 1
- 208000010747 Hodgkins lymphoma Diseases 0.000 description 1
- 241000598436 Human T-cell lymphotropic virus Species 0.000 description 1
- 241000714260 Human T-lymphotropic virus 1 Species 0.000 description 1
- 206010020710 Hyperphagia Diseases 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 208000013016 Hypoglycemia Diseases 0.000 description 1
- 206010021143 Hypoxia Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 206010021567 Impulsive behaviour Diseases 0.000 description 1
- 206010021588 Inappropriate affect Diseases 0.000 description 1
- 102000004877 Insulin Human genes 0.000 description 1
- 108090001061 Insulin Proteins 0.000 description 1
- 102000003996 Interferon-beta Human genes 0.000 description 1
- 108090000467 Interferon-beta Proteins 0.000 description 1
- 208000015592 Involuntary movements Diseases 0.000 description 1
- 208000007766 Kaposi sarcoma Diseases 0.000 description 1
- 208000008839 Kidney Neoplasms Diseases 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 1
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 1
- 208000034693 Laceration Diseases 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- 241000222722 Leishmania <genus> Species 0.000 description 1
- 208000004554 Leishmaniasis Diseases 0.000 description 1
- 206010024229 Leprosy Diseases 0.000 description 1
- 241000186781 Listeria Species 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 241000883511 Lophophora williamsii Species 0.000 description 1
- DDWFXDSYGUXRAY-UHFFFAOYSA-N Luciferin Natural products CCc1c(C)c(CC2NC(=O)C(=C2C=C)C)[nH]c1Cc3[nH]c4C(=C5/NC(CC(=O)O)C(C)C5CC(=O)O)CC(=O)c4c3C DDWFXDSYGUXRAY-UHFFFAOYSA-N 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- 208000031422 Lymphocytic Chronic B-Cell Leukemia Diseases 0.000 description 1
- 241000712899 Lymphocytic choriomeningitis mammarenavirus Species 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- 206010026673 Malignant Pleural Effusion Diseases 0.000 description 1
- 206010025538 Malignant ascites Diseases 0.000 description 1
- 102100037812 Medium-wave-sensitive opsin 1 Human genes 0.000 description 1
- 206010027406 Mesothelioma Diseases 0.000 description 1
- 102100038352 Metabotropic glutamate receptor 3 Human genes 0.000 description 1
- 102000005741 Metalloproteases Human genes 0.000 description 1
- 108010006035 Metalloproteases Proteins 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- JEYCTXHKTXCGPB-UHFFFAOYSA-N Methaqualone Chemical compound CC1=CC=CC=C1N1C(=O)C2=CC=CC=C2N=C1C JEYCTXHKTXCGPB-UHFFFAOYSA-N 0.000 description 1
- FQISKWAFAHGMGT-SGJOWKDISA-M Methylprednisolone sodium succinate Chemical compound [Na+].C([C@@]12C)=CC(=O)C=C1[C@@H](C)C[C@@H]1[C@@H]2[C@@H](O)C[C@]2(C)[C@@](O)(C(=O)COC(=O)CCC([O-])=O)CC[C@H]21 FQISKWAFAHGMGT-SGJOWKDISA-M 0.000 description 1
- SIDLZWOQUZRBRU-UHFFFAOYSA-N Methyprylon Chemical compound CCC1(CC)C(=O)NCC(C)C1=O SIDLZWOQUZRBRU-UHFFFAOYSA-N 0.000 description 1
- 208000005314 Multi-Infarct Dementia Diseases 0.000 description 1
- 208000034578 Multiple myelomas Diseases 0.000 description 1
- 241001529936 Murinae Species 0.000 description 1
- 241000186362 Mycobacterium leprae Species 0.000 description 1
- 241000187479 Mycobacterium tuberculosis Species 0.000 description 1
- 208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 description 1
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 description 1
- 102100038610 Myeloperoxidase Human genes 0.000 description 1
- 108090000235 Myeloperoxidases Proteins 0.000 description 1
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 1
- JAGRWTLXHSHWRT-UHFFFAOYSA-N NC1=CC(NS(=O)(=O)C2=CC(C(=O)O)=CC(C(=O)O)=C2)=CC=C1Cl Chemical compound NC1=CC(NS(=O)(=O)C2=CC(C(=O)O)=CC(C(=O)O)=C2)=CC=C1Cl JAGRWTLXHSHWRT-UHFFFAOYSA-N 0.000 description 1
- FWHGIPXLXHLHME-WDYSDLKTSA-N N[C@@H](CCC(=O)O)C(=O)O.O=C(O)CC[C@H](NC(=O)[C@H](CC(=O)O)N=[Ac])C(=O)O.O=C(O)C[C@H](N=[Ac])C(=O)O Chemical compound N[C@@H](CCC(=O)O)C(=O)O.O=C(O)CC[C@H](NC(=O)[C@H](CC(=O)O)N=[Ac])C(=O)O.O=C(O)C[C@H](N=[Ac])C(=O)O FWHGIPXLXHLHME-WDYSDLKTSA-N 0.000 description 1
- 239000007832 Na2SO4 Substances 0.000 description 1
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 1
- 208000028389 Nerve injury Diseases 0.000 description 1
- 206010029260 Neuroblastoma Diseases 0.000 description 1
- 108090000189 Neuropeptides Proteins 0.000 description 1
- 102000003797 Neuropeptides Human genes 0.000 description 1
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 1
- 208000015914 Non-Hodgkin lymphomas Diseases 0.000 description 1
- GGGNPWOMFMUJSO-UHFFFAOYSA-N O=C(O)C1=CC(C(=O)O)=CC(S(=O)(=O)NC2=CC=C(Cl)C([N+](=O)[O-])=C2)=C1 Chemical compound O=C(O)C1=CC(C(=O)O)=CC(S(=O)(=O)NC2=CC=C(Cl)C([N+](=O)[O-])=C2)=C1 GGGNPWOMFMUJSO-UHFFFAOYSA-N 0.000 description 1
- GMWHMNFGPBTUFR-UHFFFAOYSA-M O=C(O)C1=CC=C(C(=O)O)C(SOOO[Na])=C1 Chemical compound O=C(O)C1=CC=C(C(=O)O)C(SOOO[Na])=C1 GMWHMNFGPBTUFR-UHFFFAOYSA-M 0.000 description 1
- 208000021384 Obsessive-Compulsive disease Diseases 0.000 description 1
- 208000022873 Ocular disease Diseases 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- 206010030155 Oesophageal carcinoma Diseases 0.000 description 1
- 206010030348 Open-Angle Glaucoma Diseases 0.000 description 1
- 241000606693 Orientia tsutsugamushi Species 0.000 description 1
- 206010033128 Ovarian cancer Diseases 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
- 206010033307 Overweight Diseases 0.000 description 1
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 1
- 229910018830 PO3H Inorganic materials 0.000 description 1
- 229910018828 PO3H2 Inorganic materials 0.000 description 1
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 1
- 206010033664 Panic attack Diseases 0.000 description 1
- NFHFRUOZVGFOOS-UHFFFAOYSA-N Pd(PPh3)4 Substances [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 1
- 208000002471 Penile Neoplasms Diseases 0.000 description 1
- 206010034299 Penile cancer Diseases 0.000 description 1
- ABLZXFCXXLZCGV-UHFFFAOYSA-N Phosphorous acid Chemical class OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 206010035226 Plasma cell myeloma Diseases 0.000 description 1
- 241000233870 Pneumocystis Species 0.000 description 1
- 208000005384 Pneumocystis Pneumonia Diseases 0.000 description 1
- 206010073755 Pneumocystis jirovecii pneumonia Diseases 0.000 description 1
- 208000037062 Polyps Diseases 0.000 description 1
- 208000006664 Precursor Cell Lymphoblastic Leukemia-Lymphoma Diseases 0.000 description 1
- 102000029797 Prion Human genes 0.000 description 1
- 108091000054 Prion Proteins 0.000 description 1
- 208000024777 Prion disease Diseases 0.000 description 1
- 206010036790 Productive cough Diseases 0.000 description 1
- 208000004403 Prostatic Hyperplasia Diseases 0.000 description 1
- 208000033796 Pseudophakia Diseases 0.000 description 1
- 208000028017 Psychotic disease Diseases 0.000 description 1
- 206010037520 Pupillary block Diseases 0.000 description 1
- 208000037673 Rare dementia Diseases 0.000 description 1
- 206010038389 Renal cancer Diseases 0.000 description 1
- 206010063837 Reperfusion injury Diseases 0.000 description 1
- 208000013616 Respiratory Distress Syndrome Diseases 0.000 description 1
- 201000000582 Retinoblastoma Diseases 0.000 description 1
- 241000606697 Rickettsia prowazekii Species 0.000 description 1
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 1
- 241000607142 Salmonella Species 0.000 description 1
- 206010039491 Sarcoma Diseases 0.000 description 1
- 208000032023 Signs and Symptoms Diseases 0.000 description 1
- 208000000453 Skin Neoplasms Diseases 0.000 description 1
- 206010041250 Social phobia Diseases 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 208000021712 Soft tissue sarcoma Diseases 0.000 description 1
- 206010041591 Spinal osteoarthritis Diseases 0.000 description 1
- 206010042008 Stereotypy Diseases 0.000 description 1
- 208000005718 Stomach Neoplasms Diseases 0.000 description 1
- ZSJLQEPLLKMAKR-UHFFFAOYSA-N Streptozotocin Natural products O=NN(C)C(=O)NC1C(O)OC(CO)C(O)C1O ZSJLQEPLLKMAKR-UHFFFAOYSA-N 0.000 description 1
- 208000013200 Stress disease Diseases 0.000 description 1
- 231100000643 Substance intoxication Toxicity 0.000 description 1
- UCKMPCXJQFINFW-UHFFFAOYSA-N Sulphide Chemical compound [S-2] UCKMPCXJQFINFW-UHFFFAOYSA-N 0.000 description 1
- 201000009594 Systemic Scleroderma Diseases 0.000 description 1
- 206010042953 Systemic sclerosis Diseases 0.000 description 1
- 230000024932 T cell mediated immunity Effects 0.000 description 1
- 208000031673 T-Cell Cutaneous Lymphoma Diseases 0.000 description 1
- 210000001744 T-lymphocyte Anatomy 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- SEQDDYPDSLOBDC-UHFFFAOYSA-N Temazepam Chemical compound N=1C(O)C(=O)N(C)C2=CC=C(Cl)C=C2C=1C1=CC=CC=C1 SEQDDYPDSLOBDC-UHFFFAOYSA-N 0.000 description 1
- 208000024313 Testicular Neoplasms Diseases 0.000 description 1
- 206010057644 Testis cancer Diseases 0.000 description 1
- JZRWCGZRTZMZEH-UHFFFAOYSA-N Thiamine Natural products CC1=C(CCO)SC=[N+]1CC1=CN=C(C)N=C1N JZRWCGZRTZMZEH-UHFFFAOYSA-N 0.000 description 1
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 1
- ZMZDMBWJUHKJPS-UHFFFAOYSA-M Thiocyanate anion Chemical compound [S-]C#N ZMZDMBWJUHKJPS-UHFFFAOYSA-M 0.000 description 1
- 208000024770 Thyroid neoplasm Diseases 0.000 description 1
- 206010070863 Toxicity to various agents Diseases 0.000 description 1
- 241000223997 Toxoplasma gondii Species 0.000 description 1
- 201000005485 Toxoplasmosis Diseases 0.000 description 1
- 208000031674 Traumatic Acute Stress disease Diseases 0.000 description 1
- 206010044565 Tremor Diseases 0.000 description 1
- 241000223109 Trypanosoma cruzi Species 0.000 description 1
- 206010044708 Trypanosomal infections Diseases 0.000 description 1
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 1
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 1
- 208000002495 Uterine Neoplasms Diseases 0.000 description 1
- 206010046851 Uveitis Diseases 0.000 description 1
- 208000036826 VIIth nerve paralysis Diseases 0.000 description 1
- 201000004810 Vascular dementia Diseases 0.000 description 1
- 206010047163 Vasospasm Diseases 0.000 description 1
- 241000251539 Vertebrata <Metazoa> Species 0.000 description 1
- 208000036142 Viral infection Diseases 0.000 description 1
- 208000004354 Vulvar Neoplasms Diseases 0.000 description 1
- 208000008383 Wilms tumor Diseases 0.000 description 1
- 206010048010 Withdrawal syndrome Diseases 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 239000002250 absorbent Substances 0.000 description 1
- 230000002745 absorbent Effects 0.000 description 1
- 150000001241 acetals Chemical class 0.000 description 1
- 125000000641 acridinyl group Chemical group C1(=CC=CC2=NC3=CC=CC=C3C=C12)* 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 208000026345 acute stress disease Diseases 0.000 description 1
- 208000009956 adenocarcinoma Diseases 0.000 description 1
- WNLRTRBMVRJNCN-UHFFFAOYSA-L adipate(2-) Chemical compound [O-]C(=O)CCCCC([O-])=O WNLRTRBMVRJNCN-UHFFFAOYSA-L 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 125000003158 alcohol group Chemical group 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 229940072056 alginate Drugs 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001350 alkyl halides Chemical class 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 230000007815 allergy Effects 0.000 description 1
- PMMURAAUARKVCB-UHFFFAOYSA-N alpha-D-ara-dHexp Natural products OCC1OC(O)CC(O)C1O PMMURAAUARKVCB-UHFFFAOYSA-N 0.000 description 1
- AWUCVROLDVIAJX-UHFFFAOYSA-N alpha-glycerophosphate Natural products OCC(O)COP(O)(O)=O AWUCVROLDVIAJX-UHFFFAOYSA-N 0.000 description 1
- 229960004538 alprazolam Drugs 0.000 description 1
- VREFGVBLTWBCJP-UHFFFAOYSA-N alprazolam Chemical compound C12=CC(Cl)=CC=C2N2C(C)=NN=C2CN=C1C1=CC=CC=C1 VREFGVBLTWBCJP-UHFFFAOYSA-N 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 239000003194 amino acid receptor blocking agent Substances 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 230000003109 amnesic effect Effects 0.000 description 1
- 229940025084 amphetamine Drugs 0.000 description 1
- 230000003444 anaesthetic effect Effects 0.000 description 1
- 208000007502 anemia Diseases 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 239000003957 anion exchange resin Substances 0.000 description 1
- 208000008303 aniridia Diseases 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 239000002249 anxiolytic agent Substances 0.000 description 1
- 230000000949 anxiolytic effect Effects 0.000 description 1
- 229940005530 anxiolytics Drugs 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 229940009098 aspartate Drugs 0.000 description 1
- 208000015802 attention deficit-hyperactivity disease Diseases 0.000 description 1
- 230000002238 attenuated effect Effects 0.000 description 1
- 230000001363 autoimmune Effects 0.000 description 1
- LMEKQMALGUDUQG-UHFFFAOYSA-N azathioprine Chemical compound CN1C=NC([N+]([O-])=O)=C1SC1=NC=NC2=C1NC=N2 LMEKQMALGUDUQG-UHFFFAOYSA-N 0.000 description 1
- 229960002170 azathioprine Drugs 0.000 description 1
- 125000003828 azulenyl group Chemical group 0.000 description 1
- 210000003719 b-lymphocyte Anatomy 0.000 description 1
- 229940125717 barbiturate Drugs 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 239000011324 bead Substances 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 1
- 229940050390 benzoate Drugs 0.000 description 1
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 230000036983 biotransformation Effects 0.000 description 1
- 230000004397 blinking Effects 0.000 description 1
- 230000036770 blood supply Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 210000000133 brain stem Anatomy 0.000 description 1
- 125000004369 butenyl group Chemical group C(=CCC)* 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- MIOPJNTWMNEORI-UHFFFAOYSA-N camphorsulfonic acid Chemical compound C1CC2(CS(O)(=O)=O)C(=O)CC1C2(C)C MIOPJNTWMNEORI-UHFFFAOYSA-N 0.000 description 1
- 229940095731 candida albicans Drugs 0.000 description 1
- 229940055022 candida parapsilosis Drugs 0.000 description 1
- 125000000609 carbazolyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3NC12)* 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 206010007776 catatonia Diseases 0.000 description 1
- 230000034196 cell chemotaxis Effects 0.000 description 1
- 230000024245 cell differentiation Effects 0.000 description 1
- 230000004709 cell invasion Effects 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 230000002490 cerebral effect Effects 0.000 description 1
- 208000026106 cerebrovascular disease Diseases 0.000 description 1
- 201000010881 cervical cancer Diseases 0.000 description 1
- 208000036319 cervical spondylosis Diseases 0.000 description 1
- 229960004782 chlordiazepoxide Drugs 0.000 description 1
- ANTSCNMPPGJYLG-UHFFFAOYSA-N chlordiazepoxide Chemical compound O=N=1CC(NC)=NC2=CC=C(Cl)C=C2C=1C1=CC=CC=C1 ANTSCNMPPGJYLG-UHFFFAOYSA-N 0.000 description 1
- 210000003161 choroid Anatomy 0.000 description 1
- 238000007813 chromatographic assay Methods 0.000 description 1
- 208000032852 chronic lymphocytic leukemia Diseases 0.000 description 1
- 230000037326 chronic stress Effects 0.000 description 1
- 210000004240 ciliary body Anatomy 0.000 description 1
- 230000001886 ciliary effect Effects 0.000 description 1
- 125000000259 cinnolinyl group Chemical group N1=NC(=CC2=CC=CC=C12)* 0.000 description 1
- 230000009194 climbing Effects 0.000 description 1
- 229960003920 cocaine Drugs 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 229940126208 compound 22 Drugs 0.000 description 1
- 210000002808 connective tissue Anatomy 0.000 description 1
- 230000001054 cortical effect Effects 0.000 description 1
- IDLFZVILOHSSID-OVLDLUHVSA-N corticotropin Chemical compound C([C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](C(C)C)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC(N)=O)C(=O)NCC(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)NC(=O)[C@@H](N)CO)C1=CC=C(O)C=C1 IDLFZVILOHSSID-OVLDLUHVSA-N 0.000 description 1
- 229960000258 corticotropin Drugs 0.000 description 1
- 210000000695 crystalline len Anatomy 0.000 description 1
- 201000007241 cutaneous T cell lymphoma Diseases 0.000 description 1
- ZXIJMRYMVAMXQP-UHFFFAOYSA-N cycloheptene Chemical compound C1CCC=CCC1 ZXIJMRYMVAMXQP-UHFFFAOYSA-N 0.000 description 1
- 229960004397 cyclophosphamide Drugs 0.000 description 1
- 231100000409 cytocidal Toxicity 0.000 description 1
- 230000000445 cytocidal effect Effects 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 229940127089 cytotoxic agent Drugs 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 231100000858 damage to nervous tissue Toxicity 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000007850 degeneration Effects 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 231100000868 delusion Toxicity 0.000 description 1
- 230000006866 deterioration Effects 0.000 description 1
- 150000008050 dialkyl sulfates Chemical class 0.000 description 1
- 229960003529 diazepam Drugs 0.000 description 1
- AAOVKJBEBIDNHE-UHFFFAOYSA-N diazepam Chemical compound N=1CC(=O)N(C)C2=CC=C(Cl)C=C2C=1C1=CC=CC=C1 AAOVKJBEBIDNHE-UHFFFAOYSA-N 0.000 description 1
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 150000002009 diols Chemical class 0.000 description 1
- GAFRWLVTHPVQGK-UHFFFAOYSA-N dipentyl sulfate Chemical class CCCCCOS(=O)(=O)OCCCCC GAFRWLVTHPVQGK-UHFFFAOYSA-N 0.000 description 1
- 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 1
- 208000022602 disease susceptibility Diseases 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 125000004119 disulfanediyl group Chemical group *SS* 0.000 description 1
- 125000003438 dodecyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- MOTZDAYCYVMXPC-UHFFFAOYSA-N dodecyl hydrogen sulfate Chemical compound CCCCCCCCCCCCOS(O)(=O)=O MOTZDAYCYVMXPC-UHFFFAOYSA-N 0.000 description 1
- 229940043264 dodecyl sulfate Drugs 0.000 description 1
- 239000000890 drug combination Substances 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 239000000428 dust Substances 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 238000002635 electroconvulsive therapy Methods 0.000 description 1
- 230000004406 elevated intraocular pressure Effects 0.000 description 1
- 230000002996 emotional effect Effects 0.000 description 1
- 230000001804 emulsifying effect Effects 0.000 description 1
- 238000003821 enantio-separation Methods 0.000 description 1
- 210000003038 endothelium Anatomy 0.000 description 1
- 210000000871 endothelium corneal Anatomy 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 239000002532 enzyme inhibitor Substances 0.000 description 1
- 229940125532 enzyme inhibitor Drugs 0.000 description 1
- 201000004101 esophageal cancer Diseases 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- 229960004447 ethchlorvynol Drugs 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 230000036251 extravasation Effects 0.000 description 1
- 238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 1
- 230000035558 fertility Effects 0.000 description 1
- 239000000835 fiber Substances 0.000 description 1
- 210000002950 fibroblast Anatomy 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- GVEPBJHOBDJJJI-UHFFFAOYSA-N fluoranthrene Natural products C1=CC(C2=CC=CC=C22)=C3C2=CC=CC3=C1 GVEPBJHOBDJJJI-UHFFFAOYSA-N 0.000 description 1
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 description 1
- GNBHRKFJIUUOQI-UHFFFAOYSA-N fluorescein Chemical compound O1C(=O)C2=CC=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 GNBHRKFJIUUOQI-UHFFFAOYSA-N 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 201000010175 gallbladder cancer Diseases 0.000 description 1
- 206010017758 gastric cancer Diseases 0.000 description 1
- 208000029364 generalized anxiety disease Diseases 0.000 description 1
- 210000004602 germ cell Anatomy 0.000 description 1
- 210000004907 gland Anatomy 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 201000005442 glossopharyngeal neuralgia Diseases 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 230000000848 glutamatergic effect Effects 0.000 description 1
- 229960002972 glutethimide Drugs 0.000 description 1
- 230000003394 haemopoietic effect Effects 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 239000000380 hallucinogen Substances 0.000 description 1
- 235000015220 hamburgers Nutrition 0.000 description 1
- 201000010536 head and neck cancer Diseases 0.000 description 1
- 208000014829 head and neck neoplasm Diseases 0.000 description 1
- 210000003958 hematopoietic stem cell Anatomy 0.000 description 1
- 230000011132 hemopoiesis Effects 0.000 description 1
- 230000002440 hepatic effect Effects 0.000 description 1
- 208000006454 hepatitis Diseases 0.000 description 1
- 231100000283 hepatitis Toxicity 0.000 description 1
- MNWFXJYAOYHMED-UHFFFAOYSA-N heptanoic acid Chemical compound CCCCCCC(O)=O MNWFXJYAOYHMED-UHFFFAOYSA-N 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 1
- 102000046689 human FOLH1 Human genes 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- BICAGYDGRXJYGD-UHFFFAOYSA-N hydrobromide;hydrochloride Chemical compound Cl.Br BICAGYDGRXJYGD-UHFFFAOYSA-N 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- ZMZDMBWJUHKJPS-UHFFFAOYSA-N hydrogen thiocyanate Natural products SC#N ZMZDMBWJUHKJPS-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 1
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 1
- 201000001421 hyperglycemia Diseases 0.000 description 1
- 230000002218 hypoglycaemic effect Effects 0.000 description 1
- 230000007954 hypoxia Effects 0.000 description 1
- 230000000642 iatrogenic effect Effects 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 230000001024 immunotherapeutic effect Effects 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000000099 in vitro assay Methods 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 1
- 125000003454 indenyl group Chemical group C1(C=CC2=CC=CC=C12)* 0.000 description 1
- 125000003387 indolinyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 description 1
- 125000003406 indolizinyl group Chemical group C=1(C=CN2C=CC=CC12)* 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 208000000509 infertility Diseases 0.000 description 1
- 230000036512 infertility Effects 0.000 description 1
- 231100000535 infertility Toxicity 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 229940125396 insulin Drugs 0.000 description 1
- 210000002660 insulin-secreting cell Anatomy 0.000 description 1
- 229960001388 interferon-beta Drugs 0.000 description 1
- 238000007917 intracranial administration Methods 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007913 intrathecal administration Methods 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 210000000554 iris Anatomy 0.000 description 1
- 208000012947 ischemia reperfusion injury Diseases 0.000 description 1
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 239000012948 isocyanate Substances 0.000 description 1
- 150000002513 isocyanates Chemical class 0.000 description 1
- 125000000904 isoindolyl group Chemical group C=1(NC=C2C=CC=CC12)* 0.000 description 1
- 125000000555 isopropenyl group Chemical group [H]\C([H])=C(\*)C([H])([H])[H] 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 1
- 150000003854 isothiazoles Chemical class 0.000 description 1
- 150000002545 isoxazoles Chemical class 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 230000000366 juvenile effect Effects 0.000 description 1
- 206010023332 keratitis Diseases 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 201000010982 kidney cancer Diseases 0.000 description 1
- 210000003292 kidney cell Anatomy 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 150000002617 leukotrienes Chemical class 0.000 description 1
- 210000004558 lewy body Anatomy 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 231100000863 loss of memory Toxicity 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 210000002751 lymph Anatomy 0.000 description 1
- 210000004698 lymphocyte Anatomy 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 238000002595 magnetic resonance imaging Methods 0.000 description 1
- 208000024714 major depressive disease Diseases 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 230000007257 malfunction Effects 0.000 description 1
- 230000036210 malignancy Effects 0.000 description 1
- 230000003211 malignant effect Effects 0.000 description 1
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 1
- 201000001441 melanoma Diseases 0.000 description 1
- 210000004379 membrane Anatomy 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 230000003340 mental effect Effects 0.000 description 1
- 230000006996 mental state Effects 0.000 description 1
- 108010038445 metabotropic glutamate receptor 3 Proteins 0.000 description 1
- 229910021645 metal ion Inorganic materials 0.000 description 1
- 230000001394 metastastic effect Effects 0.000 description 1
- 208000037819 metastatic cancer Diseases 0.000 description 1
- 208000011575 metastatic malignant neoplasm Diseases 0.000 description 1
- 229960001252 methamphetamine Drugs 0.000 description 1
- MYWUZJCMWCOHBA-VIFPVBQESA-N methamphetamine Chemical compound CN[C@@H](C)CC1=CC=CC=C1 MYWUZJCMWCOHBA-VIFPVBQESA-N 0.000 description 1
- 229960002803 methaqualone Drugs 0.000 description 1
- 229960000485 methotrexate Drugs 0.000 description 1
- OYWDFLIPTKVKKY-UHFFFAOYSA-N methyl 6-nitro-1,3-benzodioxole-5-carboxylate Chemical compound C1=C([N+]([O-])=O)C(C(=O)OC)=CC2=C1OCO2 OYWDFLIPTKVKKY-UHFFFAOYSA-N 0.000 description 1
- 229960004584 methylprednisolone Drugs 0.000 description 1
- 229960000316 methyprylon Drugs 0.000 description 1
- 238000001690 micro-dialysis Methods 0.000 description 1
- 201000007309 middle cerebral artery infarction Diseases 0.000 description 1
- 235000013336 milk Nutrition 0.000 description 1
- 210000004080 milk Anatomy 0.000 description 1
- 239000008267 milk Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000036651 mood Effects 0.000 description 1
- 230000002969 morbid Effects 0.000 description 1
- 201000006417 multiple sclerosis Diseases 0.000 description 1
- 201000000585 muscular atrophy Diseases 0.000 description 1
- 201000006938 muscular dystrophy Diseases 0.000 description 1
- 230000017311 musculoskeletal movement, spinal reflex action Effects 0.000 description 1
- 206010028417 myasthenia gravis Diseases 0.000 description 1
- 208000022155 mycobacterium avium complex disease Diseases 0.000 description 1
- 201000005962 mycosis fungoides Diseases 0.000 description 1
- 210000003007 myelin sheath Anatomy 0.000 description 1
- 125000001421 myristyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- KVBGVZZKJNLNJU-UHFFFAOYSA-M naphthalene-2-sulfonate Chemical compound C1=CC=CC2=CC(S(=O)(=O)[O-])=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-M 0.000 description 1
- 125000004593 naphthyridinyl group Chemical group N1=C(C=CC2=CC=CN=C12)* 0.000 description 1
- 239000004081 narcotic agent Substances 0.000 description 1
- 230000001613 neoplastic effect Effects 0.000 description 1
- 230000008764 nerve damage Effects 0.000 description 1
- 210000001640 nerve ending Anatomy 0.000 description 1
- 210000000653 nervous system Anatomy 0.000 description 1
- 230000002981 neuropathic effect Effects 0.000 description 1
- 239000004090 neuroprotective agent Substances 0.000 description 1
- 231100000189 neurotoxic Toxicity 0.000 description 1
- 230000002887 neurotoxic effect Effects 0.000 description 1
- 229960002715 nicotine Drugs 0.000 description 1
- SNICXCGAKADSCV-UHFFFAOYSA-N nicotine Natural products CN1CCCC1C1=CC=CN=C1 SNICXCGAKADSCV-UHFFFAOYSA-N 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 208000019180 nutritional disease Diseases 0.000 description 1
- HYDZPXNVHXJHBG-UHFFFAOYSA-N o-benzylhydroxylamine;hydron;chloride Chemical compound Cl.NOCC1=CC=CC=C1 HYDZPXNVHXJHBG-UHFFFAOYSA-N 0.000 description 1
- 229940005483 opioid analgesics Drugs 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 235000013348 organic food Nutrition 0.000 description 1
- 201000008968 osteosarcoma Diseases 0.000 description 1
- 210000001672 ovary Anatomy 0.000 description 1
- 235000020830 overeating Nutrition 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- 229960004535 oxazepam Drugs 0.000 description 1
- ADIMAYPTOBDMTL-UHFFFAOYSA-N oxazepam Chemical compound C12=CC(Cl)=CC=C2NC(=O)C(O)N=C1C1=CC=CC=C1 ADIMAYPTOBDMTL-UHFFFAOYSA-N 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 239000006179 pH buffering agent Substances 0.000 description 1
- 201000002528 pancreatic cancer Diseases 0.000 description 1
- 208000008443 pancreatic carcinoma Diseases 0.000 description 1
- 230000036961 partial effect 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
- 201000003042 peeling skin syndrome Diseases 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 210000000578 peripheral nerve Anatomy 0.000 description 1
- 208000027232 peripheral nervous system disease Diseases 0.000 description 1
- 210000004303 peritoneum Anatomy 0.000 description 1
- 230000002085 persistent effect Effects 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- YNPNZTXNASCQKK-UHFFFAOYSA-N phenanthrene Chemical compound C1=CC=C2C3=CC=CC=C3C=CC2=C1 YNPNZTXNASCQKK-UHFFFAOYSA-N 0.000 description 1
- 125000001791 phenazinyl group Chemical group C1(=CC=CC2=NC3=CC=CC=C3N=C12)* 0.000 description 1
- 125000001484 phenothiazinyl group Chemical group C1(=CC=CC=2SC3=CC=CC=C3NC12)* 0.000 description 1
- 125000001644 phenoxazinyl group Chemical group C1(=CC=CC=2OC3=CC=CC=C3NC12)* 0.000 description 1
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 1
- 239000002953 phosphate buffered saline Substances 0.000 description 1
- 125000005541 phosphonamide group Chemical group 0.000 description 1
- 150000003017 phosphorus Chemical class 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 description 1
- 230000010287 polarization Effects 0.000 description 1
- 238000002600 positron emission tomography Methods 0.000 description 1
- 231100000683 possible toxicity Toxicity 0.000 description 1
- 208000028173 post-traumatic stress disease Diseases 0.000 description 1
- NNFCIKHAZHQZJG-UHFFFAOYSA-N potassium cyanide Chemical compound [K+].N#[C-] NNFCIKHAZHQZJG-UHFFFAOYSA-N 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 208000025638 primary cutaneous T-cell non-Hodgkin lymphoma Diseases 0.000 description 1
- 238000004393 prognosis Methods 0.000 description 1
- 201000008752 progressive muscular atrophy Diseases 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 210000004908 prostatic fluid Anatomy 0.000 description 1
- 230000009979 protective mechanism Effects 0.000 description 1
- 230000003304 psychophysiological effect Effects 0.000 description 1
- 125000001042 pteridinyl group Chemical group N1=C(N=CC2=NC=CN=C12)* 0.000 description 1
- 208000005069 pulmonary fibrosis Diseases 0.000 description 1
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 1
- KOUKXHPPRFNWPP-UHFFFAOYSA-N pyrazine-2,5-dicarboxylic acid;hydrate Chemical compound O.OC(=O)C1=CN=C(C(O)=O)C=N1 KOUKXHPPRFNWPP-UHFFFAOYSA-N 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003072 pyrazolidinyl group Chemical group 0.000 description 1
- 125000002755 pyrazolinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000001725 pyrenyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 239000002534 radiation-sensitizing agent Substances 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 230000003252 repetitive effect Effects 0.000 description 1
- 230000029058 respiratory gaseous exchange Effects 0.000 description 1
- 210000001525 retina Anatomy 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- PYWVYCXTNDRMGF-UHFFFAOYSA-N rhodamine B Chemical compound [Cl-].C=12C=CC(=[N+](CC)CC)C=C2OC2=CC(N(CC)CC)=CC=C2C=1C1=CC=CC=C1C(O)=O PYWVYCXTNDRMGF-UHFFFAOYSA-N 0.000 description 1
- 230000001020 rhythmical effect Effects 0.000 description 1
- 210000003296 saliva Anatomy 0.000 description 1
- 231100000241 scar Toxicity 0.000 description 1
- 230000037390 scarring Effects 0.000 description 1
- 210000004116 schwann cell Anatomy 0.000 description 1
- 230000009291 secondary effect Effects 0.000 description 1
- 210000001625 seminal vesicle Anatomy 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 238000002603 single-photon emission computed tomography Methods 0.000 description 1
- 210000002027 skeletal muscle Anatomy 0.000 description 1
- 201000000849 skin cancer Diseases 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- AWUCVROLDVIAJX-GSVOUGTGSA-N sn-glycerol 3-phosphate Chemical compound OC[C@@H](O)COP(O)(O)=O AWUCVROLDVIAJX-GSVOUGTGSA-N 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
- 208000002320 spinal muscular atrophy Diseases 0.000 description 1
- 208000005801 spondylosis Diseases 0.000 description 1
- 238000013222 sprague-dawley male rat Methods 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 210000003802 sputum Anatomy 0.000 description 1
- 208000024794 sputum Diseases 0.000 description 1
- 206010041823 squamous cell carcinoma Diseases 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 201000005428 steroid-induced glaucoma Diseases 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 239000000021 stimulant Substances 0.000 description 1
- 201000011549 stomach cancer Diseases 0.000 description 1
- 229960001052 streptozocin Drugs 0.000 description 1
- 238000000859 sublimation Methods 0.000 description 1
- 230000008022 sublimation Effects 0.000 description 1
- 231100000736 substance abuse Toxicity 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 150000003456 sulfonamides Chemical class 0.000 description 1
- 125000001273 sulfonato group Chemical group [O-]S(*)(=O)=O 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 210000004243 sweat Anatomy 0.000 description 1
- 230000035900 sweating Effects 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 210000002504 synaptic vesicle Anatomy 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 210000001138 tear Anatomy 0.000 description 1
- 229960003188 temazepam Drugs 0.000 description 1
- 230000002123 temporal effect Effects 0.000 description 1
- VCMJCVGFSROFHV-WZGZYPNHSA-N tenofovir disoproxil fumarate Chemical compound OC(=O)\C=C\C(O)=O.N1=CN=C2N(C[C@@H](C)OCP(=O)(OCOC(=O)OC(C)C)OCOC(=O)OC(C)C)C=NC2=C1N VCMJCVGFSROFHV-WZGZYPNHSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 201000003120 testicular cancer Diseases 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000003039 tetrahydroisoquinolinyl group Chemical group C1(NCCC2=CC=CC=C12)* 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- SWFSRMBSDMJGOK-UHFFFAOYSA-N thiadiazol-4-ol Chemical class OC1=CSN=N1 SWFSRMBSDMJGOK-UHFFFAOYSA-N 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- KYMBYSLLVAOCFI-UHFFFAOYSA-N thiamine Chemical compound CC1=C(CCO)SCN1CC1=CN=C(C)N=C1N KYMBYSLLVAOCFI-UHFFFAOYSA-N 0.000 description 1
- 235000019157 thiamine Nutrition 0.000 description 1
- 229960003495 thiamine Drugs 0.000 description 1
- 239000011721 thiamine Substances 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 150000003568 thioethers Chemical class 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
- 210000000115 thoracic cavity Anatomy 0.000 description 1
- 201000002510 thyroid cancer Diseases 0.000 description 1
- 210000002972 tibial nerve Anatomy 0.000 description 1
- 208000016686 tic disease Diseases 0.000 description 1
- PHWBOXQYWZNQIN-UHFFFAOYSA-N ticlopidine Chemical compound ClC1=CC=CC=C1CN1CC(C=CS2)=C2CC1 PHWBOXQYWZNQIN-UHFFFAOYSA-N 0.000 description 1
- 229960005001 ticlopidine Drugs 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 230000000472 traumatic effect Effects 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- QIWRFOJWQSSRJZ-UHFFFAOYSA-N tributyl(ethenyl)stannane Chemical compound CCCC[Sn](CCCC)(CCCC)C=C QIWRFOJWQSSRJZ-UHFFFAOYSA-N 0.000 description 1
- BDZBKCUKTQZUTL-UHFFFAOYSA-N triethyl phosphite Chemical compound CCOP(OCC)OCC BDZBKCUKTQZUTL-UHFFFAOYSA-N 0.000 description 1
- 206010044652 trigeminal neuralgia Diseases 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 125000005455 trithianyl group Chemical group 0.000 description 1
- 208000029387 trophoblastic neoplasm Diseases 0.000 description 1
- ZDPHROOEEOARMN-UHFFFAOYSA-N undecanoic acid Chemical compound CCCCCCCCCCC(O)=O ZDPHROOEEOARMN-UHFFFAOYSA-N 0.000 description 1
- 229930195735 unsaturated hydrocarbon Natural products 0.000 description 1
- 201000005112 urinary bladder cancer Diseases 0.000 description 1
- 206010046766 uterine cancer Diseases 0.000 description 1
- 206010046885 vaginal cancer Diseases 0.000 description 1
- 208000013139 vaginal neoplasm Diseases 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 210000005166 vasculature Anatomy 0.000 description 1
- 230000002227 vasoactive effect Effects 0.000 description 1
- 201000010653 vesiculitis Diseases 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 230000001755 vocal effect Effects 0.000 description 1
- 230000021542 voluntary musculoskeletal movement Effects 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
- 230000004584 weight gain Effects 0.000 description 1
- 235000019786 weight gain Nutrition 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
- 230000029663 wound healing Effects 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/06—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
-
- 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
- A61P13/08—Drugs for disorders of the urinary system of the prostate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A61P27/06—Antiglaucoma agents or miotics
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/38—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino groups bound to acyclic carbon atoms and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/52—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton
- C07C229/54—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton with amino and carboxyl groups bound to carbon atoms of the same non-condensed six-membered aromatic ring
- C07C229/60—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton with amino and carboxyl groups bound to carbon atoms of the same non-condensed six-membered aromatic ring with amino and carboxyl groups bound in meta- or para- positions
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
- C07C235/70—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton
- C07C235/72—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atoms of the carboxamide groups bound to acyclic carbon atoms
- C07C235/80—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atoms of the carboxamide groups bound to acyclic carbon atoms having carbon atoms of carboxamide groups and keto groups bound to the same carbon atom, e.g. acetoacetamides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C259/00—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups
- C07C259/04—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids
- C07C259/06—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids having carbon atoms of hydroxamic groups bound to hydrogen atoms or to acyclic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C259/00—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups
- C07C259/04—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids
- C07C259/10—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids having carbon atoms of hydroxamic groups bound to carbon atoms of six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C317/00—Sulfones; Sulfoxides
- C07C317/44—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
- C07C323/10—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton
- C07C323/11—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
- C07C323/12—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
- C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
- C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
- C07C323/56—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton containing six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
- C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
- C07C323/62—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C63/00—Compounds having carboxyl groups bound to a carbon atoms of six-membered aromatic rings
- C07C63/307—Monocyclic tricarboxylic acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C63/00—Compounds having carboxyl groups bound to a carbon atoms of six-membered aromatic rings
- C07C63/68—Compounds having carboxyl groups bound to a carbon atoms of six-membered aromatic rings containing halogen
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C65/00—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C65/01—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups
- C07C65/03—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups monocyclic and having all hydroxy or O-metal groups bound to the ring
- C07C65/05—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups monocyclic and having all hydroxy or O-metal groups bound to the ring o-Hydroxy carboxylic acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C65/00—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C65/32—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing keto groups
- C07C65/40—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing keto groups containing singly bound oxygen-containing groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D307/52—Radicals substituted by nitrogen atoms not forming part of a nitro radical
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
- C07F9/3804—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)] not used, see subgroups
- C07F9/3834—Aromatic acids (P-C aromatic linkage)
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
- C07F9/3804—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)] not used, see subgroups
- C07F9/3882—Arylalkanephosphonic acids
Definitions
- the present invention relates to new compounds, pharmaceutical compositions comprising such compounds, and methods of using such compounds to inhibit NAALADase enzyme activity, detecting diseases where NAALADase levels are altered, inhibit angiogenesis, effect neuronal activity, and treat glutamate abnormalities, neuropathy, pain, prostate diseases, cancers, TGF- ⁇ abnormalities, compulsive disorders, glaucoma, and diabetes.
- the present invention further relates to method for detecting a disease, disorder, or condition where NAALADase levels are altered, comprising:
- FIG. 14 is a bar graph plotting the withdrawal latency difference scores of normal (unoperated) rats and chronic constrictive injury-induced rats treated with a vehicle or Compound C, against the days following surgery.
- FIG. 16B is a bar graph plotting the sensory nerve conduction velocity of non-diabetic rats and STZ-diabetic rats treated with a vehicle or Compound D, against the weeks following administration with STZ.
- Compound A refers to 2-[[(2,3,4,5,6-pentafluorobenzyl)hydroxyphosphinyl]methyl]pentanedioic acid.
- “Pharmaceutically acceptable equivalent” includes, without limitation, pharmaceutically acceptable salts, hydrates, metabolites, prodrugs and isosteres. Many pharmaceutically acceptable equivalents are expected to have the same or similar in vitro or in vivo activity as the compounds of the invention.
- “Pharmaceutically acceptable salt” refers to a salt of the inventive compounds which possesses the desired pharmacological activity and which is neither biologically nor otherwise undesirable.
- the salt can be formed with acids that include, without limitation, acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride hydrobromide, hydroiodide, 2-hydroxyethane-sulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, thio
- “Isomers” refer to compounds having the same number and kind of atoms, and hence the same molecular weight, but differing with respect to the arrangement or configuration of the atoms.
- Enantiomer-enriched refers to a mixture in which one enantiomer predominates.
- Racemic mixture means a mixture containing equal amounts of individual enantiomers.
- Angiogenesis-dependent disease includes, without limitation, rheumatoid arthritis, cardiovascular diseases, neovascular diseases of the eye, peripheral vascular disorders, dermatologic ulcers and cancerous tumor growth, invasion, and metastasis.
- glutamate abnormality refers to any disease, disorder, or condition in which glutamate is implicated, including pathological conditions involving elevated levels of glutamate.
- glutamate abnormalities include, without limitation, glaucoma, spinal cord injury, epilepsy, stroke, Alzheimer's disease, Parkinson's disease, ALS, Huntington's disease, schizophrenia, pain, ischemia, peripheral neuropathy (including but not limited to diabetic neuropathy), traumatic brain injury, neuronal insult, inflammatory diseases, anxiety, anxiety disorders, memory impairment, and compulsive disorders.
- Ischemia refers to localized tissue anemia due to obstruction of the inflow of arterial blood.
- Global ischemia occurs when blood flow ceases for a period of time, as may result from cardiac arrest.
- Focal ischemia occurs when a portion of the body, such as the brain, is deprived of its normal blood supply, such as may result from thromboembolytic occlusion of a cerebral vessel, traumatic head injury, edema or brain tumor. Even if transient, both global and focal ischemia can produce widespread neuronal damage.
- nerve tissue damage occurs over hours or even days following the onset of ischemia, some permanent nerve tissue damage may develop in the initial minutes following cessation of blood flow to the brain.
- Brain damage may occur, for example, after a classical stroke or as a result of an anaesthetic accident, head trauma, hypoglycemia, carbon monoxide poisoning, lithium intoxication, vitamin (B 1 , thiamine, and B 12 ) deficiency, or excessive alcohol use.
- Korsakoff's amnesic psychosis is a rare disorder characterized by profound memory loss and confabulation, whereby the patient invents stories to conceal his or her memory loss. It is frequently associated with excessive alcohol intake. Memory impairment may furthermore be age-associated; the ability to recall information such as names, places and words seems to decrease with increasing age. Transient memory loss may also occur in patients, suffering from a major depressive disorder, after electro-convulsive therapy.
- Mental disorder refers to any clinically significant behavioral or psychological syndrome characterized by the presence of distressing symptoms or significant impairment of functioning. Mental disorders are assumed to result from some psychological or organic dysfunction of the individual; the concept does not include disturbances that are essentially conflicts between the individual and society (social deviance).
- Neuro insult refers to any damage to nervous tissue and any disability or death resulting therefrom.
- the cause of nervous insult may be metabolic, toxic, neurotoxic, iatrogenic, thermal or chemical, and includes without limitation ischemia, hypoxia, cerebrovascular accident, trauma, surgery, pressure, mass effect, hemorrhage, radiation, vasospasm, neurodegenerative disease, neurodegenerative process, infection, Parkinson's disease, ALS, myelination/demyelination processes, epilepsy, cognitive disorder, glutamate abnormality and secondary effects thereof.
- TGF- ⁇ refers to transforming growth factor beta TGF- ⁇ is recognized as a prototype of multifunctional growth factors. It regulates various cell and tissue functions, including cell growth and differentiation, angiogenesis, wound healing, immune function, extracellular matrix production, cell chemotaxis, apoptosis and hematopoiesis.
- “Therapeutic window of opportunity” or “window” refers, in relation to stroke, to the maximal delay between the onset of stroke and the initiation of efficacious therapy.
- “Dependence” refers to a maladaptive pattern of substance use, leading to clinically significant impairment or distress. Dependence is typically characterized by tolerance and/or withdrawal. Substances for which dependence may be developed include, without limitation, depressants (opioids, synthetic narcotics, barbiturates, glutethimide, methyprylon, ethchlorvynol, methaqualone, alcohol); anxiolytics (diazepam, chlordiazepoxide, alprazolam, oxazepam, temazepam); stimulants (amphetamine, methamphetamine, cocaine); and hallucinogens (LSD, mescaline, peyote, marijuana).
- depressants opioid, synthetic narcotics, barbiturates, glutethimide, methyprylon, ethchlorvynol, methaqualone, alcohol
- anxiolytics diazepam, chlordiazepoxid
- “Withdrawal” refers to a syndrome characterized by untoward physical changes that occur following cessation of or reduction in substance use, or administration of a pharmacologic antagonist.
- X is oriented meta relative to C-1, and Y is oriented ortho relative to X and para relative to C-1. More preferably, W is a bond, —(CH 2 ) n —NH—(CH 2 ) m — or —(CH 2 ) n —; m is 1-3; n is 0-3; and Z is —CO 2 H, —NO 2 , —NH 2 , —SO 3 H, halo, C 5 -C 6 heteroaryl, carboxyphenylthio, or mono- or dicarboxyphenylsulfonyl.
- the present invention further relates to a method for treating a TGF- ⁇ abnormality in an animal or a mammal, comprising administering to said animal or mammal an effective amount of a compound of formula I, as defined above.
- Preferred TGF- ⁇ abnormalities to be treated are neurodegenerative disorders, extracellular matrix formation disorders, cell-growth related diseases, infectious diseases, immune related diseases, epithelial tissue scarring, collagen vascular diseases, fibroproliferative disorders, connective tissue disorders, inflammation, inflammatory diseases, respiratory distress syndrome, infertility, and diabetes.
- Preferred inflammatory diseases to be treated are associated with PSS, polymyositis, scleroderma, dermatomyositis, eosinophilic fascitis, morphea, Raynaud's syndrome, interstitial pulmonary fibrosis, scleroderma, systemic lupus erythematosus, diabetic nephropathy, kidney disease, proliferative vitreoretinopathy, liver cirrhosis, biliary fibrosis, myelofibrosis, mesangial proliferative glomerulonephritis, crescentic glomerulonephritis, diabetic neuropathy, renal interstitial fibrosis, renal fibrosis in transplant patients receiving cyclosporin, or HIV-associated nephropathy.
- the present invention also relates to a pharmaceutical composition
- a pharmaceutical composition comprising:
- any administration regimen well known to an ordinarily skilled artisan for regulating the timing and sequence of drug delivery can be used and repeated as necessary to effect treatment
- Such regimen may include pretreatment and/or co-administration with additional therapeutic agents.
- the compounds of the present invention can be co-administered with one or more therapeutic agents either (i) together in a single formulation, or (ii) separately in individual formulations designed for optimal release rates of their respective active agent.
- Each formulation may contain from about 0.01% to about 99.99% by weight, preferably from about 3.5% to about 60% by weight, of a compound of the present invention, as well as one or more pharmaceutical excipients, such as wetting, emulsifying, and pH buffering agents.
- a NAALADase inhibitor, Compound C was added to ischemia cell cultures to determine its effect on TGF- ⁇ levels during stroke.
- the experimental data, set forth in FIGS. 1 and 2 show increased concentrations of TGF- ⁇ 1 ( FIG. 1 ) and TGF- ⁇ 2 ( FIG. 2 ) in ischemic cell cultures treated with Compound C.
- the results indicate that NAALADase inhibition promotes the release of endogenous TGF- ⁇ 's from glial cells, which in turn provides neuroprotection for neighboring neurons.
- mice Male Sprague-Dawley rats (200-225 g) were rendered diabetic by intravenous administration of streptozotocin (“STZ”, 70 mg/kg in phosphate buffered saline). Diabetic animals were divided into five groups: one group receiving Compound A (10 mg/kg or 1 mg/kg), Compound D (10 mg/kg or 1 mg/kg) or vehicle. Another group of animals (non-STZ treated) served as non-diabetic controls. Drug/vehicle treatment was started in diabetic animals 45 days post-STZ administration. STZ-induced diabetic rats were tested for sensitivity to a heat source as soon as blood glucose levels rose to 320 mg/dl or above (30 days post STZ).
- STZ streptozotocin
- the testing consists of directing an infrared heat source onto the dorsal surface of the rat hindpaw and noting the time taken for the animal to remove its paw (for detailed method, see Hargreaves et al., J. Biol. Chem. 1988 Dec. 25; 263(36): 19392-7). Each animal was tested 8 times and the mean withdrawal latency noted.
- results are graphically presented in FIG. 17 .
- the results show that diabetic rats displayed a hyperalgesia (shorter response latency) compared to non-diabetic controls.
- Diabetic drug-treated rats both Compound D and Compound A displayed longer withdrawal latencies than diabetic vehicle-treated rats, starting after 4 weeks of treatment and persisting through the six months of treatment.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Molecular Biology (AREA)
- Biochemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Engineering & Computer Science (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Ophthalmology & Optometry (AREA)
- Physical Education & Sports Medicine (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Neurology (AREA)
- Urology & Nephrology (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
New benzenedicarboxylic acid derivative compounds; pharmaceutical compositions, diagnostic methods, and diagnostic kits that include those compounds; and methods of using those compounds for inhibiting NAALADase enzyme activity, detecting diseases where NAALADase levels are altered, effecting neuronal activity, effecting TGF-β activity, inhibiting angiogenesis, and treating glutamate abnormalities, neuropathy, pain, compulsive disorders, prostate diseases, cancers, and glaucoma.
Description
- The present invention relates to new compounds, pharmaceutical compositions comprising such compounds, and methods of using such compounds to inhibit NAALADase enzyme activity, detecting diseases where NAALADase levels are altered, inhibit angiogenesis, effect neuronal activity, and treat glutamate abnormalities, neuropathy, pain, prostate diseases, cancers, TGF-β abnormalities, compulsive disorders, glaucoma, and diabetes.
- The NAALADase enzyme, also known as prostate specific membrane antigen (“PSM” or “PSMA”) and human glutamate carboxypeptidase II (“GCP II”), catalyzes the hydrolysis of the neuropeptide N-acetyl-aspartyl-glutamate (“NAAG”) to N-acetyl-aspartate (“NAA”) and glutamate. Based upon amino acid sequence homology, NAALADase has been assigned to the M28 family of peptidases.
- Studies suggest NAALADase inhibitors may be effective in treating ischemia, spinal cord injury, demyelinating diseases, Parkinson's disease, Amyotrophic Lateral Sclerosis (“ALS”), alcohol dependence, nicotine dependence, cocaine dependence, cancer, diabetic neuropathy, pain and schizophrenia, and in inhibiting angiogenesis. In view of their broad range of potential applications, a need exists for new NAALADase inhibitors and pharmaceutical compositions comprising such compounds.
-
-
- or a pharmaceutically acceptable equivalent, wherein:
- X is —W-Z;
- W is a bond or a linking group;
- Z is a terminal group; and
- Y is POOH oriented meta or para relative to C-1.
- or a pharmaceutically acceptable equivalent, wherein:
- Additionally, the present invention relates to a method for inhibiting NAALADase enzyme activity, treating a glutamate abnormality, effecting a neuronal activity (e.g., treating peripheral neuropathy or neuropathic pain), treating a prostate disease, treating cancer, inhibiting angiogenesis, or effecting a TGF-β activity, comprising administering to a mammal in need of such inhibition, treatment, or effect, an effective amount of a compound of formula I, as described above.
- The present invention further relates to method for detecting a disease, disorder, or condition where NAALADase levels are altered, comprising:
-
- (i) contacting a sample of bodily tissue or fluid with a compound of formula I, as defined above, wherein said compound binds to any NAALADase in said sample; and
- (ii) measuring the amount of any NAALADase bound to said sample, wherein the amount of NAALADase is diagnostic for said disease, disorder or condition.
- The present invention further relates to a method for detecting a disease, disorder or condition where NAALADase levels are altered in an animal or a mammal, comprising:
-
- (i) labeling a compound of formula I, as defined above, with an imaging reagent;
- (ii) administering to said animal or mammal an effective amount of the labeled compound;
- (iii) allowing said labeled compound to localize and bind to NAALADase present in said animal or mammal; and
- (iv) measuring the amount of NAALADase bound to said labeled compound, wherein the amount of NAALADase is diagnostic for said disease, disorder or condition.
- The present invention further relates to a diagnostic kit for detecting a disease, disorder or condition where NAALADase levels are altered, comprising a compound of formula I, as defined above, labeled with a marker.
- The invention further relates to a pharmaceutical composition comprising:
-
- (i) an effective amount of a compound of formula I or a pharmaceutically acceptable equivalent; and
- (ii) a pharmaceutically acceptable carrier.
-
FIG. 1 is a bar graph showing the effect of Compound C on TGF-β1 concentrations in ischemic cell cultures. -
FIG. 2 is a bar graph showing the effect of Compound C on TGF-β2 concentrations in ischemic cell cultures. -
FIG. 3 is a bar graph showing the reversal of the neuroprotective effect of Compound C by TGF-β neutralizing antibodies in ischemic cell cultures. -
FIG. 4 is a bar graph showing the non-reversal of the neuroprotective effect of Compound C by FGF neutralizing antibodies in ischemic cell cultures -
FIG. 5 is a bar graph showing the reversal of the neuroprotective effect of Compound C by TGF-β neutralizing antibodies in rats subjected to middle cerebral artery occlusion (“MCAO”). -
FIG. 6 is a bar graph showing the effect of Compound C on TGF-β1 levels during occlusion and reperfusion in rats subjected to MCAO. -
FIG. 7 is a graph plotting withdrawal latency of diabetic rats against the days following treatment with Compound A. -
FIG. 8 is a graph plotting the formalin-induced flinching behavior of rats treated with a vehicle or Compound C against the time following treatment. -
FIG. 9 is a bar graph plotting the acetic acid-induced writhing of rats treated with various doses of Compound C or a vehicle. -
FIG. 10 is a bar graph plotting the acetic acid-induced writhing of rats treated with various doses of Compound A or a vehicle. -
FIG. 11 is a bar graph plotting the acetic acid-induced writhing of rats treated with various doses of Compound D or a vehicle. -
FIG. 12 is a bar graph plotting the chronic constrictive injury-induced hyperalgesia of rats treated with a vehicle or Compound C against the days after dosing. -
FIG. 13A is a bar graph plotting the withdrawal latency difference scores of non-diabetic rats and STZ-diabetic rats treated with a vehicle or Compound A, against the days following administration with STZ. -
FIG. 13B is a bar graph plotting the withdrawal latency difference scores of non-diabetic rats and STZ-diabetic rats treated with a vehicle or Compound D, against the days following administration with STZ. -
FIG. 14 is a bar graph plotting the withdrawal latency difference scores of normal (unoperated) rats and chronic constrictive injury-induced rats treated with a vehicle or Compound C, against the days following surgery. -
FIG. 15A is a bar graph plotting the motor nerve conduction velocity of non-diabetic rats and STZ-diabetic rats treated with a vehicle or Compound A, against the weeks following administration with STZ. -
FIG. 15B is a bar graph plotting the sensory nerve conduction velocity of non-diabetic rats and STZ-diabetic rats treated with a vehicle or Compound A, against the weeks following administration with STZ. -
FIG. 16A is a bar graph plotting the motor nerve conduction velocity of non-diabetic rats and STZ-diabetic rats treated with a vehicle or Compound D, against the weeks following administration with STZ. -
FIG. 16B is a bar graph plotting the sensory nerve conduction velocity of non-diabetic rats and STZ-diabetic rats treated with a vehicle or Compound D, against the weeks following administration with STZ. -
FIG. 17 is a graph plotting the withdrawal latency of non-diabetic rats and BB/W diabetic rats treated with a vehicle, Compound D, or Compound A, against the weeks of treatment. -
FIG. 18 is a graph plotting the nerve conduction velocity of non-diabetic rats and BB/W diabetic rats treated with a vehicle, Compound D, or Compound A, against the weeks of treatment. - “Compound A” refers to 2-[[(2,3,4,5,6-pentafluorobenzyl)hydroxyphosphinyl]methyl]pentanedioic acid.
- “Compound B” refers to 2-(3-sulfanylpropyl)pentanedioic acid.
- “Compound C” refers to 2-(phosphonomethyl)pentanedioic acid (“PMPA”).
- “Compound D” refers to 2-(2-sulfanylethyl)pentanedioic acid.
- “Alkyl” refers to a branched or unbranched saturated hydrocarbon chain comprising a designated number of carbon atoms. For example, C1-C9 alkyl is a straight or branched hydrocarbon chain containing 1 to 9 carbon atoms, and includes but is not limited to substituents such as methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, n-pentyl, n-hexyl, and the like, unless otherwise indicated.
- “Alkenyl” refers to a branched or unbranched unsaturated hydrocarbon chain comprising a designated number of carbon atoms. For example, C2-C9 alkenyl is a straight or branched hydrocarbon chain containing 2 to 9 carbon atoms having at least one double bond, and includes but is not limited to substituents such as ethenyl, propenyl, iso-propenyl, butenyl, iso-butenyl, tert-butenyl, n-pentenyl, n-hexenyl, and the like, unless otherwise indicated.
- “Alkoxy” refers to the group —OR wherein R is alkyl as herein defined. Preferably, R is a branched or unbranched saturated hydrocarbon chain containing 1 to 9 carbon atoms.
- “Carbocycle” refers to a hydrocarbon, cyclic moiety having one or more closed ring(s) that is/are alicyclic, aromatic, fused and/or bridged. Examples include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclopentene, cyclohexene, cycloheptene, cycloctene, benzyl, naphthene, anthracene, phenanthracene, biphenyl and pyrene.
- “Aryl” refers to an aromatic, hydrocarbon cyclic moiety having one or more closed rings. Examples include, without limitation, phenyl, benzyl, naphthyl, anthracenyl, phenanthracenyl, biphenyl, furanyl, and pyrenyl.
- “Heterocycle” refers to a cyclic moiety having one or more closed rings that is/are alicyclic, aromatic, fused and/or bridged, with one or more heteroatoms (for example, sulfur, nitrogen or oxygen) in at least one of the rings. Examples include, without limitation, pyrrolidine, pyrrole, thiazole, thiophene, piperidine, pyridine, isoxazolidine and isoxazole.
- “Heteroaryl” refers to an aromatic, cyclic moiety having one or more closed rings with one or more heteroatoms (for example, sulfur, nitrogen or oxygen) in at least one of the rings. Examples include, without limitation, pyrrole, thiophene, pyridine and isoxazole.
- “Linking group” refers to a moiety that connects the metal binding group with the benzene ring in the compound of formula I, without compromising the pharmacological or biological activity of the overall compound.
- “Metal binding group” refers to a functional group capable of interacting with metal ion(s), such as Co2+, Ni2+, Mn2+, Cu2+, Zn2+, Mg2+, Fe2+, Fe3+, or Al3+. Metal binding groups include without limitation amines (e.g., ethylenediamine), aldehydes, ketones, carboxylic acids (e.g., ethylenediaminetetraacetic acid (“EDTA”)), thiols, phosphorus derivatives and hydroxamic acids.
- “Derivative” refers to a substance produced from another substance either directly or by modification or partial substitution.
- “Effective amount” refers to the amount required to inhibit NAALADase enzyme activity, treat a glutamate abnormality, effect a neuronal activity, treat diabetic neuropathy, pain, prostate disease, and cancer, inhibit angiogenesis, and treat a TGF-β abnormality, a compulsive disorder, glaucoma, and diabetes.
- “Electromagnetic radiation” includes without limitation radiation having a wavelength of 10−20 to 100 m. Examples include, without limitation, gamma radiation (10−20 to 10−13 m), x-ray radiation (10−11 to 10−9 m), ultraviolet light (10 nm to 400 nm), visible light (400 nm to 700 nm), infrared radiation (700 nm to 1.0 mm) and microwave radiation (1 mm to 30 cm).
- “Halo” refers to at least one fluoro, chloro, bromo, or iodo moiety.
- “Isosteres” refer to elements, functional groups, substitutents, molecules or ions having different molecular formulae but exhibiting similar or identical physical properties. For example, tetrazole is an isostere of carboxylic acid because it mimics the properties of carboxylic acid even though they have different molecular formulae. Typically, two isosteric molecules have similar or identical volumes and shapes. Ideally, isosteric compounds should be isomorphic and able to co-crystallize. Other physical properties that isosteric compounds usually share include boiling point, density, viscosity and thermal conductivity. However, certain properties may be different: dipolar moments, polarity, polarization, size and shape since the external orbitals may be hybridized differently. The term “isosteres” encompass “bioisosteres.”
- “Bioisosteres” are isosteres that, in addition to their physical similarities, share some common biological properties. Typically, bioisosteres interact with the same recognition site or produce broadly similar biological effects.
- “Carboxylic acid isosteres” include without limitation direct derivatives such as hydroxamic acids, acyl-cyanamides and acylsulfonamides; planar acidic heterocycles such as tetrazoles, mercaptoazoles, sulfinylazoles, sulfonylazoles, isoxazoles, isothiazoles, hydroxythiadiazoles and hydroxychromes; and nonplanar sulfur- or phosphorus-derived acidic functions such as phosphinates, phosphonates, phosphonamides, sulphonates, sulphonamides, and acylsulphonamides.
- “Metabolite” refers to a substance produced by metabolism or by a metabolic process.
- “NAAG” refers to N-acetyl-aspartyl-glutamate, an important peptide component of the brain, with levels comparable to the major inhibitor neurotransmitter gamma-aminobutyric acid (“GABA”). NAAG is neuron-specific, present in synaptic vesicles and released upon neuronal stimulation in several systems presumed to be glutamatergic. Studies suggest that NAAG may function as a neurotransmitter and/or neuromodulator in the central nervous system, or as a precursor of the neurotransmitter glutamate. In addition, NAAG is an agonist at group II metabotropic glutamate receptors, specifically mGluR3 receptors; when attached to a moiety capable of inhibiting NAALADase, it is expected that metabotropic glutamate receptor ligands will provide potent and specific NAALADase inhibitors.
-
- NAALADase has been assigned to the M28 peptidase family and is also called PSM, PSMA, or GCP II, EC number 3.4.17.21. It is believed that NAALADase is a co-catalytic zinc/zinc metallopeptidase. NAALADase shows a high affinity for NAAG with a Km of 540 nM. If NAAG is a bioactive peptide, then NAALADase may serve to inactivate NAAG's synaptic action. Alternatively, if NAAG functions as a precursor for glutamate, the primary function of NAALADase may be to regulate synaptic glutamate availability.
- “Pharmaceutically acceptable carrier” refers to any carrier, diluent, excipient, wetting agent, buffering agent, suspending agent, lubricating agent, adjuvant, vehicle, delivery system, emulsifier, disintegrant, absorbent, preservative, surfactant, colorant, flavorant, or sweetener, preferably non-toxic, that would be suitable for use in a pharmaceutical composition.
- “Pharmaceutically acceptable equivalent” includes, without limitation, pharmaceutically acceptable salts, hydrates, metabolites, prodrugs and isosteres. Many pharmaceutically acceptable equivalents are expected to have the same or similar in vitro or in vivo activity as the compounds of the invention.
- “Pharmaceutically acceptable salt” refers to a salt of the inventive compounds which possesses the desired pharmacological activity and which is neither biologically nor otherwise undesirable. The salt can be formed with acids that include, without limitation, acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride hydrobromide, hydroiodide, 2-hydroxyethane-sulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, thiocyanate, tosylate and undecanoate. Examples of a base salt include ammonium salts, alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases such as dicyclohexylamine salts, N-methyl-D-glucamine, and salts with amino acids such as arginine and lysine. The basic nitrogen-containing groups can be quarternized with agents including lower alkyl halides such as methyl, ethyl, propyl and butyl chlorides, bromides and iodides; dialkyl sulfates such as dimethyl, diethyl, dibutyl and diamyl sulfates; long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; and aralkyl halides such as benzyl and phenethyl bromides.
- “Prodrug” refers to a derivative of the inventive compounds that undergoes biotransformation, such as metabolism, before exhibiting its pharmacological effect(s). The prodrug is formulated with the objective(s) of improved chemical stability, improved patient acceptance and compliance, improved bioavailability, prolonged duration of action, improved organ selectivity, improved formulation (e.g., increased hydrosolubility), and/or decreased side effects (e.g., toxicity). The prodrug can be readily prepared from the inventive compounds using methods known in the art, such as those described by Burger's Medicinal Chemistry and Drug Chemistry, Fifth Ed., Vol. 1, pp. 172-178, 949-982 (1995).
- “Radiosensitizer” refers to a low molecular weight compound administered to animals in therapeutically effective amounts to promote the treatment of diseases that are treatable with electromagnetic radiation. Diseases that are treatable with electromagnetic radiation include, without limitation, neoplastic diseases, benign and malignant tumors, and cancerous cells. Electromagnetic radiation treatment of other diseases not listed herein are also contemplated by the present invention.
- “Inhibition,” in the context of enzymes, refers to reversible enzyme inhibition such as competitive, uncompetitive, and non-competitive inhibition. Competitive, uncompetitive, and non-competitive inhibition can be distinguished by the effects of an inhibitor on the reaction kinetics of an enzyme. Competitive inhibition occurs when the inhibitor combines reversibly with the enzyme in such a way that it competes with a normal substrate for binding at the active site. The affinity between the inhibitor and the enzyme may be measured by the inhibitor constant, Ki, which is defined as:
-
- wherein [E] is the concentration of the enzyme, [I] is the concentration of the inhibitor, and [EI] is the concentration of the enzyme-inhibitor complex formed by the reaction of the enzyme with the inhibitor. Unless otherwise specified, Ki as used herein refers to the affinity between the inventive compounds and NAALADase.
- “IC50” is a related term used to define the concentration or amount of a compound that is required to cause a 50% inhibition of the target enzyme.
- “NAALADase inhibitor” refers to any compound that inhibits NAALADase enzyme activity. Preferably, a NAALADase inhibitor exhibits a Ki of less than 100 μM, more preferably less than 10 μM, and even more preferably less than 1 μM, as determined using any appropriate assay known in the art.
- “Isomers” refer to compounds having the same number and kind of atoms, and hence the same molecular weight, but differing with respect to the arrangement or configuration of the atoms.
- “Stereoisomers” are isomers that differ only in the arrangement of the atoms in space.
- “Optical isomers” refer to diastereoisomers or enantiomers.
- “Diastereoisomers” are stereoisomers that are not mirror images of each other. Diastereoisomers occur in compounds having two or more asymmetric carbon atoms; thus, such compounds have 2n optical isomers, where n is the number of asymmetric carbon atoms.
- “Enantiomers” are a pair of stereoisomers that are non-superimposable mirror images of each other. Enantiomers result from the presence of one or more asymmetric carbon atoms in the compound (e.g., glyceraldehyde, lactic acid, sugars, tartaric acid, amino acids).
- “Enantiomer-enriched” refers to a mixture in which one enantiomer predominates.
- “Racemic mixture” means a mixture containing equal amounts of individual enantiomers.
- “Non-racemic mixture” is a mixture containing unequal amounts of enantiomers.
- “Angiogenesis” refers to the process whereby new capillaries are formed. “Inhibition” of angiogenesis may be measured by many parameters in accordance with the present invention and, for instance, may be assessed by delayed appearance of neovascular structures, slowed development of neovascular structures, decreased occurrence of neovascular structures, slowed or decreased severity of angiogenesis-dependent disease effects, arrested angiogenic growth, or regression of previous angiogenic growth. In the extreme, complete inhibition is referred to herein as prevention. In relation to angiogenesis or angiogenic growth, “prevention” refers to no substantial angiogenesis or angiogenic growth if none had previously occurred, or no substantial further angiogenesis or angiogenic growth if growth had previously occurred.
- “Angiogenesis-dependent disease” includes, without limitation, rheumatoid arthritis, cardiovascular diseases, neovascular diseases of the eye, peripheral vascular disorders, dermatologic ulcers and cancerous tumor growth, invasion, and metastasis.
- “Animal” refers to a living organism having sensation and the power of voluntary movement, and which requires for its existence oxygen and organic food. Examples include, without limitation, members of the human, equine, porcine, bovine, murine, canine, or feline species. In the case of a human, an “animal” may also be referred to as a “patient.”
- “Mammal” refers to a warm-blooded vertebrate animal.
- “Anxiety” includes without limitation the unpleasant emotional state consisting of psychophysiological responses to anticipation of unreal or imagined danger, ostensibly resulting from unrecognized intrapsychic conflict. Physiological concomitants include increased heart rate, altered respiration rate, sweating, trembling, weakness, and fatigue; psychological concomitants include feelings of impending danger, powerlessness, apprehension, and tension. Dorland's Illustrated Medical Dictionary, 27th ed. (W.B. Saunders Co. 1988).
- “Anxiety Disorder” includes without limitation mental disorders in which anxiety and avoidance behavior predominate. Dorland's Illustrated Medical Dictionary, 27th ed. (W.B. Saunders Co. 1988). Examples include without limitation panic attack, agoraphobia, panic disorder, acute stress disorder, chronic stress disorder, specific phobia, simple phobia, social phobia, substance induced anxiety disorder, organic anxiety disorder, obsessive compulsive disorder, post-traumatic stress disorder, generalized anxiety disorder, and anxiety disorder NOS. Other anxiety disorders are characterized in Diagnostic and Statistical Manual of Mental Disorders, 4th ed. (American Psychiatric Association 1994).
- “Attention Deficit Disorder” (“ADD”) refers to a disorder characterized by developmentally inappropriate inattention and impulsiveness, with or without hyperactivity. Inattention means a failure to finish tasks started, easily distracted, seeming lack of attention, and difficulty concentrating on tasks requiring sustained attention. Impulsiveness means acting before thinking, difficulty taking turns, problems organizing work, and constant shifting from one activity to another. Hyperactivity means difficulty staying seated and sitting still, and running or climbing excessively.
- “Cancer” includes, without limitation, ACTH-producing tumors, acute lymphocytic leukemia, acute nonlymphocytic leukemia, cancer of the adrenal cortex, bladder cancer, brain cancer, breast cancer, cervix cancer, chronic lymphocytic leukemia, chronic myelocytic leukemia, colorectal cancer, cutaneous T-cell lymphoma, endometrial cancer, esophageal cancer, Ewing's sarcoma, gallbladder cancer, hairy cell leukemia, head and neck cancer, Hodgkin's lymphoma, Kaposi's sarcoma, kidney cancer, liver cancer, lung cancer (small and/or non-small cell), malignant peritoneal effusion, malignant pleural effusion, melanoma, mesothelioma, multiple myeloma, neuroblastoma, non-Hodgkin's lymphoma, osteosarcoma, ovary cancer, ovary (germ cell) cancer, pancreatic cancer, penis cancer, prostate cancer, retinoblastoma, skin cancer, soft-tissue sarcoma, squamous cell carcinomas, stomach cancer, testicular cancer, thyroid cancer, trophoblastic neoplasms, cancer of the uterus, vaginal cancer, cancer of the vulva, and Wilm's tumor.
- “Compulsive disorder” refers to any disorder characterized by irresistible impulsive behavior. Examples of compulsive disorders include without limitation drug dependence, eating disorders, pathological gambling, ADD, and Tourette's syndrome.
- “Demyelinating disease” refers to any disease involving damage to or removal of the myelin sheath naturally surrounding nerve tissue, such as that defined in U.S. Pat. No. 5,859,046 and International Publication No. WO 98/03178, herein incorporated by reference. Examples include without limitation peripheral demyelinating diseases (such as Guillain-Barré syndrome, peripheral neuropathies and Charcot-Marie Tooth disease) and central demyelinating diseases (such as multiple sclerosis).
- “Disease” refers to any deviation from or interruption of the normal structure or function of any part, organ or system (or combinations) of the body that is manifested by a characteristic set of symptoms and signs and whose etiology, pathology, and prognosis may be known or unknown. Dorland's Illustrated Medical Dictionary, 27th ed. (W.B. Saunders Co. 1988).
- “Disorder” refers to any derangement or abnormality of function; a morbid physical or mental state. Dorland's Illustrated Medical Dictionary, 27th ed. (W.B. Saunders Co. 1988).
- “Substance dependence” refers to a psychologic addiction or a physical tolerance to a substance. Tolerance means a need to increase the dose progressively in order to produce the effect originally achieved by smaller amounts.
- “Eating disorder” refers to compulsive overeating, obesity, or severe obesity. Obesity means body weight of 20% over standard height-weight tables. Severe obesity means over 100% overweight.
- “Glaucoma” includes without limitation chronic (idiopathic) open-angle glaucomas (e.g., high-pressure, normal-pressure); pupillary block glaucomas (e.g., acute angle-closure, subacute angle-closure, chronic angle-closure, combined-mechanism); developmental glaucomas (e.g., congenital (infantile), juvenile, Anxenfeld-Rieger syndrome, Peters' anomaly, Aniridia); glaucomas associated with other ocular disorders (e.g., glaucomas associated with disorders of the corneal endothelium, iris, ciliary body, lens, retina, choroid and vitreous); glaucomas associated with elevated episcleral venous pressure (e.g., systemic diseases with associated elevated intraocular pressure and glaucoma, corticosteroid-induced glaucoma); glaucomas associated with inflammation and trauma (e.g., glaucomas associated with keratitis, episcleritis, scleritis, uveitis, ocular trauma and hemorrhage); glaucomas following intraocular surgery, e.g., ciliary block (malignant) glaucoma, glaucomas in aphakia and pseudophakia, glaucomas associated with corneal surgery, glaucomas associated with vitreoretinal surgery.
- “Glutamate abnormality” refers to any disease, disorder, or condition in which glutamate is implicated, including pathological conditions involving elevated levels of glutamate. Examples of glutamate abnormalities include, without limitation, glaucoma, spinal cord injury, epilepsy, stroke, Alzheimer's disease, Parkinson's disease, ALS, Huntington's disease, schizophrenia, pain, ischemia, peripheral neuropathy (including but not limited to diabetic neuropathy), traumatic brain injury, neuronal insult, inflammatory diseases, anxiety, anxiety disorders, memory impairment, and compulsive disorders.
- “Ischemia” refers to localized tissue anemia due to obstruction of the inflow of arterial blood. Global ischemia occurs when blood flow ceases for a period of time, as may result from cardiac arrest. Focal ischemia occurs when a portion of the body, such as the brain, is deprived of its normal blood supply, such as may result from thromboembolytic occlusion of a cerebral vessel, traumatic head injury, edema or brain tumor. Even if transient, both global and focal ischemia can produce widespread neuronal damage. Although nerve tissue damage occurs over hours or even days following the onset of ischemia, some permanent nerve tissue damage may develop in the initial minutes following cessation of blood flow to the brain. Much of this damage is attributed to glutamate toxicity and secondary consequences of reperfusion of the tissue, such as the release of vasoactive products by damaged endothelium, and the release of cytotoxic products, such as free radicals and leukotrienes, by the damaged tissue.
- “Memory impairment” refers to a diminished mental registration, retention or recall of past experiences, knowledge, ideas, sensations, thoughts or impressions. Memory impairment may affect short and long-term information retention, facility with spatial relationships, memory (rehearsal) strategies, and verbal retrieval and production. Common causes of memory impairment are age, severe head trauma, brain anoxia or ischemia, alcoholic-nutritional diseases, drug intoxications and neurodegenerative diseases. For example, memory impairment is a common feature of neurodegenerative diseases such as Alzheimer's disease and senile dementia of the Alzheimer type. Memory impairment also occurs with other kinds of dementia such as multi-infarct dementia, a senile dementia caused by cerebrovascular deficiency, and the Lewy-body variant of Alzheimer's disease with or without association with Parkinson's disease. Creutzfeldt-Jakob disease is a rare dementia with which memory impairment is associated. It is a spongiform encephalopathy caused by the prion protein; it may be transmitted from other sufferers or may arise from gene mutations. Loss of memory is also a common feature of brain-damaged patients. Brain damage may occur, for example, after a classical stroke or as a result of an anaesthetic accident, head trauma, hypoglycemia, carbon monoxide poisoning, lithium intoxication, vitamin (B1, thiamine, and B12) deficiency, or excessive alcohol use. Korsakoff's amnesic psychosis is a rare disorder characterized by profound memory loss and confabulation, whereby the patient invents stories to conceal his or her memory loss. It is frequently associated with excessive alcohol intake. Memory impairment may furthermore be age-associated; the ability to recall information such as names, places and words seems to decrease with increasing age. Transient memory loss may also occur in patients, suffering from a major depressive disorder, after electro-convulsive therapy.
- “Mental disorder” refers to any clinically significant behavioral or psychological syndrome characterized by the presence of distressing symptoms or significant impairment of functioning. Mental disorders are assumed to result from some psychological or organic dysfunction of the individual; the concept does not include disturbances that are essentially conflicts between the individual and society (social deviance).
- “Metastasis” refers to “[t]he ability of cells of a cancer to disseminate and form new foci of growth at noncontiguous sites (i.e., to form metastases).” See Hill, RP, “Metastasis”, The Basic Science of Oncology, Tannock et al., Eds., pp. 178-195 (McGraw-Hill 1992), herein incorporated by reference. “The transition from in situ tumor growth to metastatic disease is defined by the ability of tumor cells of the primary site to invade local tissues and to cross tissue barriers. To initiate the metastatic process, carcinoma cells must first penetrate the epithelial basement membrane and then invade the interstitial stroma. For distant metastases, intravasation requires tumor cell invasion of the subendothelial basement membrane that must also be negotiated during tumor cell extravasation. The development of malignancy is also associated with tumor-induced angiogenesis [which] not only allows for expansion of the primary tumors, but also permits easy access to the vascular compartment due to defects in the basement membranes of newly formed vessels.” See Aznavoorian et al., Cancer (1993) 71: 1368-1383, herein incorporated by reference.
- “Nervous insult” refers to any damage to nervous tissue and any disability or death resulting therefrom. The cause of nervous insult may be metabolic, toxic, neurotoxic, iatrogenic, thermal or chemical, and includes without limitation ischemia, hypoxia, cerebrovascular accident, trauma, surgery, pressure, mass effect, hemorrhage, radiation, vasospasm, neurodegenerative disease, neurodegenerative process, infection, Parkinson's disease, ALS, myelination/demyelination processes, epilepsy, cognitive disorder, glutamate abnormality and secondary effects thereof.
- “Nervous tissue” refers to the various components that make up the nervous system, including without limitation neurons, neural support cells, glia, Schwann cells, vasculature contained within and supplying these structures, the central nervous system, the brain, the brain stem, the spinal cord, the junction of the central nervous system with the peripheral nervous system, the peripheral nervous system and allied structures.
- “Neuropathy” refers to any disease or malfunction of the nerves. Neuropathy includes, without limitation, peripheral neuropathy, diabetic neuropathy, autonomic neuropathy and mononeuropathy. Peripheral neuropathy may be idiopathic or induced by any causes including diseases (for example, amyloidosis, alcoholism, HIV, syphilis, virus, autoimmune disorder, cancer, porphyria, arachnoiditis, post herpetic neuralgia, Guillain-Barré syndrome, diabetes including Type I and Type II diabetes), chemicals (for example, toxins, lead, dapsone, vitamins, paclitaxel chemotherapy, HAART therapy) and physical injuries to a particular nerve or nerve plexus (for example, trauma, compression, constriction).
- “Neuroprotective” refers to the effect of reducing, arresting or ameliorating nervous insult, and protecting, resuscitating or reviving nervous tissue that has suffered nervous insult.
- “Pain” refers to localized sensations of discomfort, distress or agony, resulting from the stimulation of specialized nerve endings. It serves as a protective mechanism insofar as it induces the sufferer to remove or withdraw from the source. Dorland's Illustrated Medical Dictionary, 27th ed. (W.B. Saunders Co. 1988). Examples of pain include, without limitation, acute, chronic, cancer, burn, incisional, inflammatory, diabetic neuropathic, and back pain.
- “Neuropathic pain” refers to a condition of pain associated with a nerve injury. Depending on the particular syndrome, the pain may be due to alterations of the brain or spinal cord or may be due to abnormalities in the nerve itself. Neuropathic pain may be idiopathic or induced by any causes including diseases (for example, amyloidosis, alcoholism, HIV, syphilis, virus, autoimmune disorder, cancer, porphyria, arachnoiditis, post herpetic neuralgia, Guillain-Barré syndrome, and diabetes, including Type I and Type II diabetes), chemicals (for example, toxins, lead, dapsone, vitamins, paclitaxel chemotherapy, and HAART therapy) and physical injuries to a particular nerve or nerve plexus (for example, trauma, compression, and constriction).
- “Pathological gambling” refers to a condition characterized by a preoccupation with gambling. Similar to psychoactive substance abuse, its effects include development of tolerance with a need to gamble progressively larger amounts of money, withdrawal symptoms, and continued gambling despite severe negative effects on family and occupation.
- “Prostate disease” refers to any disease affecting the prostate. Examples of prostate disease include without limitation prostate cancer such as adenocarcinoma and metastatic cancers of the prostate; and conditions characterized by abnormal growth of prostatic epithelial cells such as benign prostatic hyperplasia.
- “Schizophrenia” refers to a mental disorder or group of mental disorders characterized by disturbances in form and content of thought (loosening of associations, delusions, hallucinations), mood (blunted, flattened, inappropriate affect), sense of self and relationship to the external world (loss of ego boundaries, dereistic thinking, and autistic withdrawal), and behavior (bizarre, apparently purposeless, and stereotyped activity or inactivity). Examples of schizophrenia include, without limitation, acute, ambulatory, borderline, catatonic, childhood, disorganized, hebephrenic, latent, nuclear, paranoid, paraphrenic, prepsychotic, process, pseudoneurotic, pseudopsychopathic, reactive, residual, schizo-affective and undifferentiated schizophrenia Dorland's Illustrated Medical Dictionary, 27th ed. (W.B. Saunders Co. 1988).
- “TGF-β” refers to transforming growth factor beta TGF-β is recognized as a prototype of multifunctional growth factors. It regulates various cell and tissue functions, including cell growth and differentiation, angiogenesis, wound healing, immune function, extracellular matrix production, cell chemotaxis, apoptosis and hematopoiesis.
- “TGF-β abnormality” refers to any disease, disorder or condition in which TGF-β is implicated, including diseases disorders and conditions characterized by an abnormal level of TGF-β.
- “Abnormal level of TGF-β” refers to a measurable variance from normal levels of TGF-β, as determined by one of ordinary skill in the art using known techniques.
- “Therapeutic window of opportunity” or “window” refers, in relation to stroke, to the maximal delay between the onset of stroke and the initiation of efficacious therapy.
- “Tourette's syndrome” refers to an autosomal multiple tic disorder characterized by compulsive swearing, multiple muscle tics and loud noises. Tics are brief, rapid, involuntary movements that can be simple or complex; they are stereotyped and repetitive, but not rhythmic. Simple tics, such as eye blinking, often begin as nervous mannerisms. Complex tics often resemble fragments of normal behavior.
- “Treating” refers to:
-
- (i) preventing a disease, disorder or condition from occurring in an animal that may be predisposed to the disease, disorder and/or condition but has not yet been diagnosed as having it;
- (ii) inhibiting the disease, disorder or condition, i.e., arresting its development; and/or
- (iii) relieving the disease, disorder or conditions i.e., causing regression of the disease, disorder and/or condition.
- “Treating substance dependence” refers to suppressing the psychologic addiction or physical tolerance to the drug of abuse, and/or relieving and/or preventing a withdrawal syndrome resulting from the drug dependence.
- “Dependence” refers to a maladaptive pattern of substance use, leading to clinically significant impairment or distress. Dependence is typically characterized by tolerance and/or withdrawal. Substances for which dependence may be developed include, without limitation, depressants (opioids, synthetic narcotics, barbiturates, glutethimide, methyprylon, ethchlorvynol, methaqualone, alcohol); anxiolytics (diazepam, chlordiazepoxide, alprazolam, oxazepam, temazepam); stimulants (amphetamine, methamphetamine, cocaine); and hallucinogens (LSD, mescaline, peyote, marijuana).
- “Tolerance” refers to an acquired reaction to a substance characterized by diminished effect with continued use of the same dose and/or a need for increased doses to achieve intoxication or desired effect previously achieved by lower doses. Both physiological and psychosocial factors may contribute to the development of tolerance. With respect to physiological tolerance, metabolic and/or functional tolerance may develop. By increasing the rate of metabolism of the substance, the body may be able to eliminate the substance more readily. Functional tolerance is defined as a decrease in sensitivity of the central nervous system to the substance.
- “Withdrawal” refers to a syndrome characterized by untoward physical changes that occur following cessation of or reduction in substance use, or administration of a pharmacologic antagonist.
- One of ordinary skill in the art will recognize that there are alternative nomenclatures, nosologies and classification systems for the diseases, disorders and conditions defined above, and that such systems evolve with medical scientific progress.
- Unless the context clearly dictates otherwise, the definitions of singular terms may be extrapolated to apply to their plural counterparts as they appear in the application; likewise, the definitions of plural terms may be extrapolated to apply to their singular counterparts as they appear in the application.
-
-
- or a pharmaceutically acceptable equivalent, wherein:
- X is —W-Z;
- W is a bond or a linking group;
- Z is a terminal group; and
- Y is —COOH oriented meta or para relative to C-1.
- Linking groups include without limitation divalent hydrocarbon chains, ethers, sulfides and amines, wherein the hydrocarbon chain, whether alone or part of the ether, sulfide or amine, may be saturated or unsaturated, straight or branched, open or closed, unsubstituted or substituted with one or more substituent(s), preferably, independently selected from the group consisting of C1-C6 alkoxy, C2-C6 alkenyloxy, phenoxy, benzyloxy, hydroxy, carboxy, carbamido, carbamoyl, carbamyl, carbonyl, carbozoyl, amino, hydroxyamino, formamido, formyl, guanyl, cyano, cyanoamino, isocyano, isocyanato, diazo, azido, hydrazino, triazano, nitrilo, isonitrilo, nitro, nitroso, isonitroso, nitrosamino, imino, nitrosimino, oxo, C1-C6 alkylthio, sulfamino, sulfamoyl, sulfeno, sulfhydryl, sulfinyl, sulfo, sulfonyl, sulfoxy, thiocarboxy, thiocyano, isothiocyano, thioformamido, halo, haloalkyl, chlorosyl, chloryl, perchloryl, trifluoromethyl, iodosyl, iodyl, phosphino, phosphinyl, phospho, phosphono, arsino, selanyl, diselanyl, siloxy, silyl and silylene.
- Preferably, W is a bond, —(CR1R2)n—, —(CR1R2)nO(CR3R4)m—, —(CR1R2)nS(CR3R4)m or —(CR1R2)nNR(CR3R4)m—, wherein m and n are independently 0-9, and R, R1, R2, R3 and R4 are independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C6-C14 aryl, heteroaryl, C6-C14 carbocycle, heterocycle, halo, hydroxy, sulfhydryl, nitro, amino or C1-C6 alkoxy, and said alkyl, alkenyl, alkynyl, aryl, heteroaryl, carbocycle, heterocycle or alkoxy is independently unsubstituted or substituted with one or more substituent(s). More preferably, R, R1, R2, R3 and R4 are each hydrogen and the total number of carbon atoms in W is 2-6.
- Preferably, Z is a metal binding group. More preferably, Z is —COOH, —COR5, —OR5, —CF3, —CN, —F, —Cl, —Br, —I, —NO, —NO2, —C(O)(NR5OR6), —C(O)(NR5PO3H2), —C(O)(NR5R6), ═NOH, —NR5(P(O)(R6)OH), ═NR5, —N═NR5, —N(R5)CN, —NR5(CR6R7)pCOOH, —NR5(CO)NR6R7, —NR5(COOR6), —NR5(CO)R6, —NR5(OR6), —NR5R6, —NR5(SO2R6), —O(CO)R5, —OR5, —SO2(OR5), —SO2(NR5R6), —SO2R5, —SO3R5, —SNR5(OR6), —S(NR5R6), —SR5, —SSR5, —P(O)(OH)OR5, —P(O)(OH)R5 or —PR5R6, wherein p is 0-6, and R5, R6 and R7 are independently hydrogen, C1-C9 alkyl, C2-C9 alkenyl, C2-C9 alkynyl, C6-C14 aryl, heteroaryl, C6-C14 carbocycle, heterocycle, halo, hydroxy, sulfhydryl, nitro, amino or C1-C9 alkoxy, and said alkyl, alkenyl, alkynyl, aryl, heteroaryl, carbocycle, heterocycle or alkoxy is independently unsubstituted or substituted with one or more substituent(s). More preferably, Z is —NH(CR6R7)pCOOH, —PO(OH)OR5, —PO(OH)R5, —NR5(P(O)(OH)R6), —CON(R5)(OH) or —SH.
- In a preferred embodiment of formula I, X is —SO2-aryl, carboxy, S-aryl, nitro, halo, amino, —SO3H, —(CR1R2)nCO2R3, —NR5(CR1R2)nCO2R3, —(C═O)-aryl, —(C═O)-phenyoxy-aryl, —(C═O)NR5-aryl, —O(CR1R2)n—S—S—(CR3R4)m-aryl, hydroxy, —(CR1R2)nNR5(CR3R4)m-heteroaryl, —NR5—(C═O)-alkyl and NR5—(C═O)-aryl; wherein m and n are independently 0-9; R1, R2, R3, R4, and R5 are independently hydrogen, C1-C6 alkyl, C2-6 alkenyl, C2-C6 alkynyl, C6-C14 aryl, heteroaryl, C6-C14 carbocycle, heterocycle, halo, hydroxy, sulfhydryl, nitro, amino or C1-C6 alkoxy, wherein said alkyl, alkenyl, alkynyl, aryl, heteroaryl, carbocycle, heterocycle or alkoxy is independently unsubstituted or substituted with one or more substituent(s).
- In another preferred embodiment of formula I:
-
- X is —(CR1R2)n(CR3R4)mCOOH, —PO(OH)OR5, —(CR1R2)nP(OH)OR5, —NH—(CR3R4)m-heteroaryl, —NH(P(O)(OH)R6), —(CR1R2)nNH(P(O)(OH)R6) —CON(R5)(OH), —(CR1R2)nCON(R5)(OH), —(CR1R2)nSH, —O(CR3R4)mSH, —SO2NH-aryl, —NR5(C═O)—(CR1R2)n(C═O)aryl, —SO2NH-aryl-N(C═O)—CH2(C═O)-aryl, —O-aryl wherein aryl in —O-aryl is substituted by at least one of nitro or carboxy, or
- wherein X is oriented meta or para to C-1;
- m and n are independently 1-3, provided that when X is —O(CR3R4)mSH, then m is 2 or 3;
- R1, R2, R3, R4, R5, and R6 are independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C6-C14 aryl, heteroaryl, C6-C14 carbocycle, heterocycle, halo, hydroxy, sulfhydryl, nitro, amino or C1-C6 alkoxy, wherein said alkyl, alkenyl, alkynyl, aryl, heteroaryl, carbocycle, heterocycle or alkoxy is independently unsubstituted or substituted with one or more substituent(s); and
- Y is —COOH oriented meta or para relative to C-1;
- and preferably, when X is —PO(OH)OR5 or —(CR1R2)nP(O)(OH)OR5, then R5 is not H or methyl; when X is —NH(P(O)(OH)R6) or —(CR1R2)nNH(P(O)(OH)R6), then R6 is not benzyl unsubstituted or substituted with amino; and when X is —CON(R5)(OH), then R5 is not H or methyl.
- X is —(CR1R2)n(CR3R4)mCOOH, —PO(OH)OR5, —(CR1R2)nP(OH)OR5, —NH—(CR3R4)m-heteroaryl, —NH(P(O)(OH)R6), —(CR1R2)nNH(P(O)(OH)R6) —CON(R5)(OH), —(CR1R2)nCON(R5)(OH), —(CR1R2)nSH, —O(CR3R4)mSH, —SO2NH-aryl, —NR5(C═O)—(CR1R2)n(C═O)aryl, —SO2NH-aryl-N(C═O)—CH2(C═O)-aryl, —O-aryl wherein aryl in —O-aryl is substituted by at least one of nitro or carboxy, or
- Possible substituents of said alkyl, alkenyl, alkynyl, aryl, heteroaryl, carbocycle, heterocycle and alkoxy include, without limitation, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C2-C6 alkenyloxy, phenoxy, benzyloxy, hydroxy, carboxy, hydroperoxy, carboxy, carbamido, carbamoyl, carbamyl, carbonyl, carbozoyl, amino, hydroxyamino, formamido, formyl, guanyl, cyano, cyanoamino, isocyano, isocyanato, diazo, azido, hydrazino, triazano, nitrilo, isonitrilo, nitro, nitroso, isonitroso, nitrosamino, imino, nitrosimino, oxo, C1-C6 alkylthio, sulfamino, sulfamoyl, sulfeno, sulfhydryl, sulfinyl, sulfo, sulfonyl, sulfoxy, thiocarboxy, thiocyano, isothiocyano, thioformamido, halo, haloalkyl, chlorosyl, chloryl, perchloryl, trifluoromethyl, iodosyl, iodyl, phosphino, phosphinyl, phospho, phosphono, arsino, selanyl, diselanyl, siloxy, silyl, silylene and carbocyclic and heterocyclic moieties. Carbocyclic moieties include alicyclic and aromatic structures.
- Examples of carbocyclic and heterocyclic moieties include, without limitation, phenyl, benzyl, naphthyl, indenyl, azulenyl, fluorenyl, anthracenyl, indolyl, isoindolyl, indolinyl, benzofuranyl, benzothiophenyl, indazolyl, benzimidazolyl, benzthiazolyl, tetrahydrofuranyl, tetrahydropyranyl, pyridyl, pyrrolyl, pyrrolidinyl, pyridinyl, pyrimidinyl, purinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl quinolizinyl, furyl, thiophenyl, imidazolyl, oxazolyl, benzoxazolyl, thiazolyl, isoxazolyl, isotriazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, trithianyl, indolizinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, thienyl, tetrahydroisoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, and phenoxazinyl.
- In a preferred embodiment of formula I, X is oriented meta relative to C-1, and Y is oriented ortho relative to X and para relative to C-1. More preferably, W is a bond, —(CH2)n—NH—(CH2)m— or —(CH2)n—; m is 1-3; n is 0-3; and Z is —CO2H, —NO2, —NH2, —SO3H, halo, C5-C6 heteroaryl, carboxyphenylthio, or mono- or dicarboxyphenylsulfonyl.
- Examples of this embodiment are set forth below in Table I.
TABLE I 2-[(4-carboxyphenyl)- sulfonyl]-1,4-benzenedi- carboxylic acid (1) 2-[(2,5-dicarboxyphenyl)- sulfonyl]-1,4-benzenedi- carboxylic acid (2) 1,2,4-benzenetricarboxylic acid (3) 2-[(2-carboxyphenyl)thio]- 1,4-benzenedicarboxylic acid (4) 2-nitro-1,4- benzenedicarboxylic acid (5) 2-bromo-1,4- benzenedicarboxylic acid (6) 2-amino-1,4- benzenedicarboxylic acid (7) 2-sulfoterephthalic acid, monosodium salt (8) 2-carboxymethyl-1,4- benzenedicarboxylic acid (9) 2-[(2-furanylmethyl)-amino]- 1,4-benzenedicarboxylic acid (10) 2-[(carboxymethyl)amino]- 1,4-benzenedicarboxylic acid (11) - In another preferred embodiment of formula I, X is oriented ortho relative to C-1, and Y is oriented para relative to X and meta relative to C-1.
- More preferably, (1) when W is a bond, then Z is —C2H, —OH, —NO2, —C(O)(NHR5), —SR5, —COR5, or NH(CH2R5), and R5 is an aryl or a heteroaryl that is independently unsubstituted or substituted with one or more alkyl, nitro or carboxy group(s); and (2) when W is —(CH2)n— and n is 1-3, then Z is —SH.
- Examples of this embodiment are set forth below in Table II.
TABLE II 4-(4-nitrobenzoyl)-1,3- benzenedicarboxylic acid (12) 4-[4-(2,4-dicarboxybenzoyl)phenoxy]- 1,2-benzenedicarboxylic acid (13) 4-[[(2,4,6-trimethylphenyl)amino]- carbonyl]-1,3-benzenedicarboxylic acid (14) 4-nitro-1,3-benzenedicarboxylic acid (15) 4-[(1-naphthalenylamino)-carbonyl]-1,3- benzenedicarboxylic acid (16) 1,2,4-benzenetricarboxylic acid (17) 4-[(2-carboxyphenyl)thio]-1,3- benzenedicarboxylic acid (18) 4-[3-[[3-(2,4-dicarboxyphenoxy)propyl]- dithio]propoxy]-1,3-benzenedicarboxylic acid (19) 4-hydroxy-1,3-benzenedicarboxylic acid (20) 4-[(2-furanylmethyl)amino]-1,3- benzenedicarboxylic acid (21) 4-(2-mercaptoethyl)-1,3- benzenedicarboxylic acid (22) - In another preferred embodiment of formula I, X is oriented meta relative to C-1, Y is oriented meta relative to X and meta relative to C-1.
- More preferably, (1) when W is a bond, —(CH2)n— or —O(CH2)m— and m and n are independently 0-3, then Z is —SO3H, —NO2, —NH2, —CO2H, —OH, —PO3H, —CO(NHOH) or —SH; (2) when W is —(CH2)nNH(CH2)m— and m and n are independently 0-3, then Z is —CO2H or C5-C6 heteroaryl; and (3) when W is a bond, then Z is either (a) a heteroaryl that is unsubstituted or substituted with an aryl that is unsubstituted or substituted with one or more C1-C3 alkyl, halo, nitro or hydroxy group(s), or (b) —SO2(NHR6) or —NH(COR6), wherein R6 is an aryl that is unsubstituted or substituted with one or more nitro, amino, halo or hydroxy group(s).
- Examples of this embodiment are set forth below in Table III.
TABLE III 5-[4,5-dihydro-5-(4-hydroxyphenyl)-3- phenyl-1H-pyrazol-1-yl]-1,3- benzenedicarboxylic acid (23) 5-(4,5-dihydro-3-methyl-5-phenyl-1H- pyrazol-1-yl)-1,3-benzenedicarboxylic acid (24) 5-[[(4-chloro-3-nitrophenyl)- amino]sulfonyl]-1,3- benzenedicaxboxylic acid (25) 5-[[[4-chloro-3-[[3-(2-methoxyphenyl)- 1,3-dioxopropyl]amino]phenyl]amino]sulfonyl- 1,3-benzenedicarboxylic acid (26) 5-[[3-[4-(acetylamino)phenyl]-1,3- dioxopropyl]amino]-1,3- benzenedicarboxylic acid (27) 5-acetylamino-1,3-benzenedicarboxylic acid (28) 5-[[(1-hydroxy-2-naphthalenyl)carbonyl]- methylamino]-1,3-benzenedicaxboxylic acid (29) 5-(4-carboxy-2-nitrophenoxy)-1,3- benzenedicarboxylic acid (30) 5-sulfo-1,3-benzenedicarboxylic acid (31) 5-nitro-1,3-benzenedicarboxylic acid (32) 5-amino-1,3-benzenedicarboxylic acid (33) 1,3,5-benzenetricarboxylic acid (34) 5-[[(3-amino-4-chlorophenyl)amino]- sulfonyl]-1,3-benzenedicaxboxylic acid (35) 5-(3-mercaptopropoxy)-1,3- benzenedicarboxylic acid (36) 5-hydroxy-1,3-benzenedicarboxylic acid (37) 5-(2-mercaptoethoxy)-1,3- benzenedicarboxylic acid (38) 5-[(hydroxyamino)-carbonyl]-1,3- benzenedicarboxylic acid (39) 5-phosphono-1,3-benzenedicarboxylic acid (40) 5-mercaptomethyl-1,3- benzenedicarboxylic acid (41) 5-phosphonomethyl-1,3- benzenedicarboxylic acid (42) 5-[[(carboxymethyl)amino]-methyl]-1,3- benzenedicarboxylic acid (43) 5-[(carboxymethyl)amino]-1,3- benzenedicarboxylic acid (44) 5-[[(2-furanylmethyl)amino]-methyl]- 1,3-benzenedicarboxylic acid (45) 5-[2-(hydroxyamino)-2-oxoethyl]-1,3- benzenedicarboxylic acid (46) 5-(2-mercaptoethyl)-1,3- benzenedicarboxylic acid (47) - The compounds of formula I possess one or more asymmetric carbon center(s) and are thus capable of existing in the form of optical isomers as well as in the form of racemic or non-racemic mixtures of optical isomers. The optical isomers can be obtained by resolution of the racemic mixtures according to conventional processes well known in the art, for example by formation of diastereoisomeric salts by treatment with an optically active acid or base and then separation of the mixture of diastereoisomers by crystallization followed by liberation of the optically active bases from these salts. Examples of appropriate acids are tartaric, diacetyltartaric, dibenzoyltartaric, ditoluoyltartaric, and camphorsulfonic acid.
- A different process for separating optical isomers involves the use of a chiral chromatography column optimally chosen to maximize the separation of the enantiomers. Still another available method involves synthesis of covalent diastereoisomeric molecules, for example, esters, amides, acetals, ketals, and the like, by reacting compounds used in the inventive methods and pharmaceutical compositions with an optically active acid in an activated form, an optically active diol or an optically active isocyanate. The synthesized diastereoisomers can be separated by conventional means such as chromatography, distillation, crystallization or sublimation, and then hydrolyzed to deliver the enantiomerically pure compound. In some cases hydrolysis to the parent optically active drug is not necessary prior to dosing the patient since the compound can behave as a prodrug. The optically active compounds of the present invention can likewise be obtained by utilizing optically active starting materials.
- It is understood that the compounds of formula I encompass individual optical isomers as well as racemic and non-racemic mixtures.
- The present invention relates to a method for inhibiting NAALADase enzyme activity in an animal or a mammal, comprising administering to said animal or mammal an effective amount of a compound of formula I, as defined above.
- The present invention further relates to a method for treating a glutamate abnormality in an animal or a mammal, comprising administering to said animal or mammal an effective amount of a compound of formula I, as defined above.
- Preferred glutamate abnormalities to be treated are compulsive disorders, stroke, demyelinating disease, schizophrenia, Parkinson's disease, ALS, diabetic neuropathy, pain, anxiety, anxiety disorders, glaucoma, and memory impairment. More preferably, the compulsive disorder is alcohol, nicotine or cocaine dependence.
- Stroke patients often experience a significant temporal delay between the onset of ischemia and the time to initiation of therapy. Thus, there is a need for neuroprotectants with a long therapeutic window of opportunity. It is expected that the compounds of formula I have a therapeutic window of opportunity of at least 1 hour. Accordingly, when the glutamate abnormality is stroke, the compound of formula I may be administered to said animal or
mammal 60 minutes, 120 minutes, or more following onset of stroke. - Without being bound to any particular mechanism of action, preferred compounds of the present invention are expected to be those that block glutamate release pre-synaptically without interacting with post-synaptic glutamate receptors. Such compounds would be devoid of the behavioral toxicities associated with post-synaptic glutamate antagonists.
- The present invention further relates to a method for effecting a neuronal activity in an animal or a mammal, comprising administering to said animal or mammal an effective amount of a compound of formula I, as defined above.
- The neuronal activity that is effected by the inventive method may be stimulation of damaged neurons, promotion of neuronal regeneration, prevention of neurodegeneration, or treatment of a neurological disorder.
- Examples of neurological disorders that are treatable by the methods of the present invention include without limitation: trigeminal neuralgia; glossopharyngeal neuralgia; Bell's Palsy, myasthenia gravis; muscular dystrophy, Amyotrophic Lateral Sclerosis (“ALS”); progressive muscular atrophy, progressive bulbar inherited muscular atrophy, herniated, ruptured or prolapsed invertebrate disk syndromes; cervical spondylosis; plexus disorders; thoracic outlet destruction syndromes; neuropathy, pain; Alzheimer's disease; Parkinson's disease; ALS; and Huntington's disease.
- The inventive method is particularly useful for treating peripheral neuropathy and neuropathic pain such as peripheral neuropathy or neuropathic pain induced by HIV, chemicals (for example, toxins, lead, dapsone, vitamins, paclitaxel chemotherapy, HAART therapy), or diabetes such as
type 1 andtype 2 diabetes. - The inventive method is also particularly useful for treating traumatic brain injury, physical damage to spinal cord, stroke associated with brain damage, demyelinating disease, and neurological disorders relating to neurodegeneration such as Alzheimer's disease, Parkinson's disease, and ALS.
- When the neurological disorder is pain, the compound of formula I is preferably administered in combination with an effective amount of morphine.
- The present invention further relates to a method for treating a prostate disease in an animal or a mammal, comprising administering to said animal or mammal an effective amount of a compound of formula I, as defined above.
- The present invention further relates to a method for treating cancer in an animal or a mammal, comprising administering to said animal or mammal an effective amount of a compound of formula I, as defined above.
- Preferred cancers to be treated are those in tissues where NAALADase resides, including without limitation the brain, kidney, and testis.
- The present invention further relates to a method for inhibiting angiogenesis in an animal or a mammal, comprising administering to said animal or mammal an effective amount of a compound of formula I, as defined above.
- Angiogenesis may be necessary for fertility or metastasis of cancer tumors, or may be related to an angiogenic-dependent disease. Thus, the inventive methods may also be useful for treating an angiogenic-dependent disease including, without limitation, rheumatoid arthritis, cardiovascular diseases, neovascular diseases of the eye, peripheral vascular disorders, dermatologic ulcers, and cancerous tumor growth, invasion, and metastasis.
- The present invention further relates to a method for treating a TGF-β abnormality in an animal or a mammal, comprising administering to said animal or mammal an effective amount of a compound of formula I, as defined above. Preferred TGF-β abnormalities to be treated are neurodegenerative disorders, extracellular matrix formation disorders, cell-growth related diseases, infectious diseases, immune related diseases, epithelial tissue scarring, collagen vascular diseases, fibroproliferative disorders, connective tissue disorders, inflammation, inflammatory diseases, respiratory distress syndrome, infertility, and diabetes.
- Preferred neurodegenerative disorders to be treated are neural tissue damage resulting from ischemia reperfusion injury, myelination, and neurodegeneration.
- Preferred cell-growth related disorders to be treated are those affecting kidney cells, hematopoietic cells, lymphocytes, epithelial cells, and endothelial cells.
- Preferred infectious diseases to be treated are those caused by a macrophage pathogen, particularly a macrophage pathogen such as bacteria, yeast, fungi, viruses, protozoa, Trypanosoma cruzi, Histoplasma capsulatum, Candida albicans, Candida parapsilosis, Cryptococcus neoformans, Salmonella, Pneumocystis, Toxoplasma, Listeria, Mycobacteria, Rickettsia, and Leishmania. Mycobacteria include without limitation Mycobacterium tuberculosis and Mycobacterium leprae. Toxoplasma includes without limitation Toxoplasma gondii. Rickettsia includes without limitation R. prowazekii, R. coronii, and R. tsutsugamushi.
- Other preferred infectious diseases to be treated are single or multiple cutaneous lesions, mucosal disease, Chagas' disease, acquired immunodeficiency syndrome (“AIDS”), toxoplasmosis, leishmaniasis, tyrpanosomiasis, shistosomiasis, cryptosporidiosis, Mycobacterium avium infections, Pneumocystis carinii pneumonia, and leprosy.
- Preferred immune related diseases to be treated are autoimmune disorders; impaired immune function; and immunosuppression associated with an infectious disease, particularly, trypanosomal infection, viral infection, human immunosuppression virus, human T cell lymphotropic virus (“HTLV-1”), lymphocytic choriomeningitis virus, or hepatitis.
- Preferred collagen vascular diseases to be treated include progressive systemic sclerosis (“PSS”), polymyositis, scleroderma, dermatomyositis, eosinophilic fascitis, morphea, Raynaud's syndrome, interstitial pulmonary fibrosis, scleroderma, and systemic lupus erythematosus.
- Preferred fibroproliferative disorders to be treated include diabetic nephropathy, kidney disease, proliferative vitreoretinopathy, liver cirrhosis, biliary fibrosis, and myelofibrosis. Especially preferred kidney diseases include mesangial proliferative glomerulonephritis, crescentic glomerulonephritis, diabetic neuropathy, renal interstitial fibrosis, renal fibrosis in transplant patients receiving cyclosporin, and HIV-associated nephropathy.
- Preferred connective tissue disorders to be treated include scleroderma, myelofibrosis, and hepatic, intraocular and pulmonary fibrosis.
- Preferred inflammatory diseases to be treated are associated with PSS, polymyositis, scleroderma, dermatomyositis, eosinophilic fascitis, morphea, Raynaud's syndrome, interstitial pulmonary fibrosis, scleroderma, systemic lupus erythematosus, diabetic nephropathy, kidney disease, proliferative vitreoretinopathy, liver cirrhosis, biliary fibrosis, myelofibrosis, mesangial proliferative glomerulonephritis, crescentic glomerulonephritis, diabetic neuropathy, renal interstitial fibrosis, renal fibrosis in transplant patients receiving cyclosporin, or HIV-associated nephropathy.
- Without being limited to any particular mechanism of action, preferred compounds of the present invention treat inflammatory diseases by regulating TGF-β and/or inhibiting myeloperoxidase.
- Other uses associated with the compounds' TGF-β regulating properties include:
-
- stimulating growth of tissue, glands or organs, particularly growth that would enhance milk production or weight gain;
- stimulating cell proliferation, particularly proliferation of fibroblasts, mesenchymal cells, or epithelial cells;
- inhibiting cell growth, particularly of epithelial cells, endothelial cells, T and B lymphocytes, and thymocytes;
- inhibiting expression of adipose, skeletal muscle and hematopoietic phenotypes, neoplasms, non-cytocidal viral or other pathogenic infections and autoimmune disorders;
- mediating disease resistance and susceptibility;
- suppressing cellular immune response;
- inhibiting scar tissue formation, preferably in skin or other epithelial tissue that has been damaged by wounds resulting from accidental injury, surgical operations, trauma-induced lacerations or other trauma, or wounds involving the peritoneum for which the excessive connective tissue formation is abdominal adhesions;
- increasing the effectiveness of a vaccine, particularly a vaccine for an allergy towards, e.g., dust or hayfever, and
- inhibiting polyp formation.
- The compounds of the present invention are useful for in vitro and in vivo diagnostic methods for detecting diseases, disorders and conditions where NAALADase levels are altered including, without limitation, neurological disorders, glutamate abnormalities, neuropathy, pain, compulsive disorders, prostate diseases, cancers and TGF-β abnormalities.
- Accordingly, the present invention also relates to a method for detecting a disease, disorder or condition where NAALADase levels are altered, comprising:
-
- (i) contacting a sample of bodily tissue or fluid with a compound of the invention, as defined above, wherein said compound binds to any NAALADase in said sample; and
- (ii) measuring the amount of any NAALADase bound to said sample, wherein the amount of NAALADase is diagnostic for said disease, disorder or condition.
- The present invention further relates to a method for detecting a disease, disorder or condition where NAALADase levels are altered in an animal or a mammal, comprising:
-
- (i) labeling a compound of the invention, as defined above, with an imaging reagent;
- (ii) administering to said animal or mammal an effective amount of the labeled compound;
- (iii) allowing said labeled compound to localize and bind to NAALADase present in said animal or mammal; and
- (iv) measuring the amount of NAALADase bound to said labeled compound, wherein the amount of NAALADase is diagnostic for said disease, disorder or condition.
- The present invention further relates to a diagnostic kit for detecting a disease, disorder or condition where NAALADase levels are altered, comprising a compound of the invention, as defined above, labeled with a marker. The kit may further comprise buffering agents, agents for reducing background interference, control reagents and/or apparatus for conducting the test.
- Examples of bodily tissues and fluids include, without limitation, prostate tissue, ejaculate, seminal vesicle fluid, prostatic fluid, urine, blood, saliva, tears, sweat, lymph and sputum.
- The compound may be labeled with a marker using techniques known in the art. Useful markers include, without limitation, enzymatic markers and imaging reagents. Examples of imaging reagents include radiolabels such as 131I, 111In, 123I, 99Tc, 32P, 125I, 3H and 14C; fluorescent labels such as fluorescein and rhodamine; and chemiluminescers such as luciferin.
- The amount of NAALADase can be measured using techniques known in the art including, without limitation, assays (such as immunometric, calorimetric, densitometric, spectrographic and chromatographic assays) and imaging techniques (such as magnetic resonance spectroscopy (MRS), magnetic resonance imaging (MRI), single-photon emission computed tomography (SPECT) and positron emission tomography (PET)).
- The amount of NAALADase can be measured in vivo using known imaging techniques, as described above.
- The relationship between NAALADase inhibitors and glutamate, and the effectiveness of NAALADase inhibitors in treating and detecting various diseases, disorders and conditions have been discussed in U.S. Pat. Nos. 5,672,592; 5,795,877; 5,804,602; 5,824,662; 5,863,536; 5,977,090; 5,981,209; 6,011,021; 6,017,903; 6,025,344; 6,025,345; 6,046,180; and 6,228,888; allowed U.S. patent application Ser. No. 09/228,391, for which the issue fee has been paid; International Publication Nos. WO 00/01668 and WO 00/38785; a U.S. Provisional Application filed on Jan. 17, 2001; and other references generally known in the art. The present inventors hereby incorporate by reference, as though set forth herein in full, the entire contents of the aforementioned patents, patent applications, and publications, particularly their discussions, figures and data regarding the effectiveness of NAALADase inhibitors in inhibiting angiogenesis, in effecting TGF-β activity, in diagnosing diseases, and in treating ischemia, spinal cord injury, demyelinating diseases, Parkinson's disease, ALS, alcohol dependence, nicotine dependence, cocaine dependence, prostate disease, cancer, diabetic neuropathy, pain, schizophrenia, anxiety, anxiety disorder, and memory impairment. The present inventors have discovered that the inventive compounds are effective NAALADase inhibitors. Thus, the inventive compounds are expected to have the same uses as the NAALADase inhibitors disclosed in the patents, patent applications, and publications that are incorporated by reference.
- The present invention also relates to a pharmaceutical composition comprising:
-
- (i) an effective amount of a compound of formula I; and
- (ii) a pharmaceutically acceptable carrier.
- Preferred compounds of formula I are set forth above.
- Preferably, the compound of formula I is present in an effective amount for inhibiting NAALADase enzyme activity, treating glutamate abnormalities, effecting neuronal activity, treating diabetic neuropathy, pain, prostate diseases, and cancers, inhibiting angiogenesis, and treating TGF-β abnormalities, compulsive disorders, and glaucoma.
- In the inventive methods, the compounds will generally be administered to a patient in the form of a pharmaceutical formulation. Such formulation preferably includes, in addition to the active agent, a physiologically acceptable carrier and/or diluent. The compounds may be administered by any means known to an ordinarily skilled artisan. For example, the compounds may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally, or via an implanted reservoir in dosage formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants, and vehicles. The term “parenteral” as used herein includes subcutaneous, intravenous, intramuscular, intraperitoneal, intrathecal, intraventricular, intrasternal, intracranial, or intraosseous injection and infusion techniques. The exact administration protocol will vary depending upon various factors including the age, body weight, general health, sex and diet of the patient; the determination of specific administration procedures would be routine to an ordinarily skilled artisan.
- To be effective therapeutically as central nervous system targets, the compounds should readily penetrate the blood-brain barrier when peripherally administered. Compounds that cannot penetrate the blood-brain barrier can be effectively administered by an intraventricular route or by other methods recognized in the art. See, e.g., U.S. Pat. Nos. 5,846,565; 5,651,986; and 5,626,862.
- The compounds and compositions of the present invention may be administered by a single dose, multiple discrete doses, or continuous infusion. The compounds are well suited to continuous infusion. Pump means, particularly subcutaneous pump means, are preferred for continuous infusion.
- Dose levels on the order of about 0.001 to about 10,000 mg/kg of the active ingredient compound are useful in the treatment of the above conditions, with preferred levels being about 0.1 to about 1,000 mg/kg, and more preferred levels being about 1 to about 100 mg/kg. The specific dose level for any particular patient will vary depending upon a variety of factors, including the activity and the possible toxicity of the specific compound employed; the age, body weight, general health, sex, and diet of the patient; the time of administration; the rate of excretion; drug combination; the severity of the particular disease being treated; and the form of administration. Typically, in vitro dosage-effect results provide useful guidance on the proper doses for patient administration. Studies in animal models are also helpful. The considerations for determining the proper dose levels are well known in the art.
- For the methods of the present invention, any administration regimen well known to an ordinarily skilled artisan for regulating the timing and sequence of drug delivery can be used and repeated as necessary to effect treatment Such regimen may include pretreatment and/or co-administration with additional therapeutic agents.
- The compounds and compositions of the present invention may be used alone or in combination with one or more additional agent(s) for simultaneous, separate, or sequential use.
- The additional agent(s) may be any therapeutic agent(s) known to an ordinarily skilled artisan, including without limitation: one or more compound(s) of formula I; steroids, for example, hydrocortisomes such as methylprednisolone; anti-inflammatory or anti-immune drugs, such as methotrexate, azathioprine, cyclophosphamide or cyclosporin A; interferon-β; antibodies, such as anti-CD4 antibodies; agents which can reduce the risk of a second ischemic event, such as ticlopidine; chemotherapeutic agents; immunotherapeutic compositions; electromagnetic radiosensitizers; and morphine.
- The compounds of the present invention can be co-administered with one or more therapeutic agents either (i) together in a single formulation, or (ii) separately in individual formulations designed for optimal release rates of their respective active agent. Each formulation may contain from about 0.01% to about 99.99% by weight, preferably from about 3.5% to about 60% by weight, of a compound of the present invention, as well as one or more pharmaceutical excipients, such as wetting, emulsifying, and pH buffering agents.
-
- The following examples are illustrative of the present invention and are not intended to be limitations thereon. Unless otherwise indicated, all percentages are based upon 100% by weight of the final composition.
- A solution of 5-bromomethyl-1,3-benzenedicarboxylate (Collman et al., J. Am. Chem. Soc., 116(14) (1994) 6245-6251; 0.315 g, 1.0 mmol) in triethylphosphite (3.0 mL) was heated at 15° C. for 5 hours. The solvent was removed under reduced pressure and the residual oil was purified by chromatography to give 0.248 g of colorless oil (67% yield).
- 1H NMR (CDCl3) δ 1.28 (t, 3H), 1.42 (t, 3H), 3.26 (d, 2H), 4.06 (q, 2H), 4.41 (q, 2H), 8.17 (s, 2H), 8.58 (s, 1H).
- TLC: Rf 0.10 (EtOAc/
Hexanes 1/1). - A solution of diethyl 5-[(diethoxyphosphinyl)methyl]-1,3-benzenedicarboxylate (0.186 g, 0.5 mmol) in 12 N HCl (2.5 mL) was heated at 100° C. for 24 hours. The resulting precipitate was washed with water and dried under vacuum to give 0.057 g of white powder (41% yield).
- 1H NMR (D2O) δ 3.11 (d, 2H), 7.93 (s, 2H), 8.19 (s, 1H).
- TLC: Rf 0.20 (EtOAc/
Hexanes 1/1). - Elemental Analysis: Calculated for C9H7O7P.H2O: C, 38.86; H, 3.99. Found: C, 38.74; H, 4.08.
- To a solution of
diethyl - 1H NMR: (CDCl3) δ 1.41 (t, 6H), 4.40 (q, 4H), 5.05 (s, 2H), 7.3-7.5 (m, 5H), 8.52 (s, 2H), 8.76 (s, 1H), 9.1 (br, 1H).
- TLC: Rf 0.62 (EtOAc/
Hexanes 1/1). - To a solution of diethyl 5-[[(phenylmethoxy)amino]-carbonyl]-1,3-benzenedicarboxylate (0.742 g, 2.0 mmol) in ethanol (10 mL) was added a suspension of Pd/C in ethanol (5 mL), and the mixture was shaken under hydrogen (50 psi) for 20 hours. The catalyst was removed by filtration through a pad of celite and the filtrate was concentrated to give white powder. This material was washed with ethanol (10 mL×2) and dried under vacuum to give 0.380 g of white powder (67% yield).
- 1H NMR: (CD3OD) δ 1.44 (t, 6H), 4.45 (q, 4H), 8.60 (s, 2H), 8.72 (s, 1H).
- TLC: Rf 0.20 (EtOAc/
Hexanes 1/1). - To a solution of diethyl 5-[(hydroxyamino)carbonyl]-1,3-benzenedicarboxylate (0.281 g, 1.0 mmol) in acetone (5 mL) was added 1.0 N NaOH (5 mL) at room temperature, and the mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure and the residue was taken up with 1 N HCl (15 mL) to give white precipitate. This material was dried under vacuum to give 0.096 g of white solid (43% yield).
- 1H NMR: (D2O) δ 8.52 (s, 2H), 8.76 (s, 1H).
- Elemental Analysis: Calculated for C9H7NO6.H2O: C, 44.45; H, 3.73; N, 5.76. Found: C, 44.47; H, 3.78; N, 5.74.
- To a solution of dimethyl 4-hydroxy-isophthalate (0.850 g, 4.04 mmol) in CH2Cl2 (15 mL) were added triethylamine (0.6 mL, 4.3 mmol) and triflic anhydride (0.8 mL, 4.76 mmol) at 0° C., and the mixture was stirred at 0° C. for 18 hours. The solvent was evaporated and the residue was diluted with ether (30 mL). The organic solution was washed with 1 N HCl (30 mL×3), dried over MgSO4, and concentrated to give 1.30 g of dark yellow oil (93% yield).
- 1H NMR: (CDCl3) δ 3.97 (s, 3H), 4.00 (s, 3H), 7.4 (d, 1H), 8.3 (d, 1H), 8.74 (s, 1H).
- To a solution of dimethyl 4-trifluoromethanesulfonyl-oxy-1,3-benzenedicarboxylate (1.5 g, 4.38 mmol) in dioxane (50 mL) were added Pd(PPh3)4 (510 mg, 0.44 mmol), lithium chloride (1.3 g, 30.7 mmol) and tributyl(vinyl)tin (1.5 mL, 5.13 mmol) at room temperature. The mixture was heated at 100° C. for 5 hours. The reaction mixture was filtered and the filtrate was concentrated and passed through a column of silica gel (Hexanes/EtOAc=10:1) to give 1.1 g of colorless oil (84% yield).
- 1H NMR: (CDCl3) δ 3.92 (s, 3H), 3.93 (s, 3H), 5.45 (d, 1H), 5.73 (d, 1H), 7.49 (m, 1H), 7.66 (d, 1H), 8.13 (d, 1H), 8.53 (s, 1H).
- To a degassed solution of dimethyl 4-ethenyl-1,3-benzenedicarboxylate (415 mg, 1.88 mmol) in benzene (6 mL) were added AIBN (33 mg, 0.21 mmol) and thioacetic acid (0.27 mL, 3.78 mmol), and the mixture was refluxed for 5 hours. The reaction mixture was diluted with aqueous NaHCO3 solution (15 mL) and extracted with EtOAc (15 mL). The organic layer was dried over MgSO4 and concentrated. The residual material was purified by silica gel chromatography (hexanes/EtOAc=10:1) to give 0.150 g of colorless oil (27% yield).
- 1H NMR: (CDCl3) δ 2.32 (s, 3H), 3.16 (t, 2H), 3.28 (t, 2H), 3.94 (s, 6H), 7.42 (d, 1H), 8.09 (d, 1H), 8.58 (s, 1H).
- To a degassed solution of dimethyl 4-[2-(acetylthio)ethyl]-1,3-benzenedicarboxylate (0.130 g, 0.44 mmol) in THF (5 mL) was added a degassed solution of 5 N NaOH (5 mL). The reaction mixture was stirred under nitrogen overnight. The reaction mixture was diluted with H2O (10 mL) and extracted with EtOAC (10 mL). The organic layer was dried over MgSO4 and concentrated to give 0.045 g of white solid (45% yield).
- 1H NMR: (DMSO) δ 2.67 (t, 2H), 3.21 (t, 2H), 7.37 (d, 1H), 7.98 (d, 1H), 8.46 (s, 1H)
- 13C NMR: (DMSO) δ 26.64, 40.60, 130.87, 132.05, 133.46, 133.81, 134.13, 148.53, 169.22, 170.20
- Elemental Analysis: Calculated for C10H10SO4.0.3 EtOAc: C, 53.24; H, 4.95; S, 12.69. Found: C, 53.37; H, 4.87; S, 12.84.
- MS(FAB): 225
- Various compounds of formula I were tested for in vitro inhibition of NAALADase activity, and the results are provided below in Table IV.
TABLE IV Compound Ki (nM) 4-[4-(2,4-dicarboxybenzoyl)phenoxy]-1,2- 1170 benzenedicarboxylic acid (13) 2-[(4-carboxyphenyl)sulfonyl]-1,4-benzenedicarboxylic 2370 acid (1) 2-[(2,5-dicarboxyphenyl)sulfonyl]-1,4- 1870 benzenedicarboxylic acid (2) 4-[(2-carboxyphenyl)thio]-1,3-benzenedicarboxylic acid 3980 (18) 2-[(2-carboxyphenyl)thio]-1,4-benzenedicarboxylic acid 572 (4) 4-[3-[[3-(2,4-dicarboxyphenoxy)-propyl]-dithio]propoxy]- 3750 1,3-benzenedicarboxylic acid (19) 5-(3-mercaptopropoxy)-1,3-benzenedicarboxylic acid (36) 3300 5-(2-mercaptoethoxy)-1,3-benzenedicarboxylic acid (38) 14500 5-[(hydroxyamino)-carbonyl]-1,3-benzenedicarboxylic 1000 acid (39) 5-phosphono-1,3-benzenedicarboxylic acid (40) 14000 5-mercaptomethyl-1,3-benzenedicarboxylic acid (41) 6500 5-phosphonomethyl-1,3-benzenedicarboxylic acid (42) 3100 5-[(carboxymethyl)amino]-1,3-benzenedicarboxylic acid 100000 (44) 5-[[(2-furanylmethyl)amino]methyl]-1,3- 50000 benzenedicarboxylic acid (45) 2-carboxymethyl-1,4-benzenedicarboxylic acid (9) 9000 5-[2-hydroxyamino)-2-oxoethyl]-1,3- 12000 benzenedicarboxylic acid (46) 4-(2-mercaptoethyl)-1,3-benzenedicarboxylic acid (22) 116 5-(2-mercaptoethyl)-1,3-benzenedicarboxylic acid (47) 5100
Protocol for Assaying In Vitro Inhibition of NAALADase Activity - The following were combined in each assay tube: 100 μL of 10 mM CoCl2, 250 μL of 200 mM Tris chloride, 100 μL tissue, 100 μL of 10 mM NAALADase inhibitor in Bakers H2O, and Bakers H2O to make a total volume of 950 μL. Each tube was then incubated for 10 minutes in a 37° C. water bath. 50 μL of 3-H-NAAG was then added to each assay tube and incubated for an additional 15 minutes in a 37° C. water bath. The assay was stopped by adding 1.0 ml of 0.1 M sodium phosphate.
- Glutamate released by the action of the NAALADase enzyme was separated from the assay solution using an anion exchange resin. The resin was equilibrated to 25° C., 2.0 ml of the resin was added to a Pasteur pipette pre-loaded with a single glass bead, and each column was washed twice with distilled H2O. A column was placed over a scintillation vial and 200 μL of an assay sample was loaded onto the column. After draining, glutamate was eluted using two 1.0 ml washes of 1 M formic acid. After addition of 10 ml of scintillation cocktail, each sample was counted for 2 minutes on a scintillation counter.
- To examine the in vitro effect of the compounds of formula I on ischemia, cortical cell cultures were treated with various compounds of formula I during an ischemic insult utilizing potassium cyanide and 2-deoxyglucose, and for one hour thereafter (for experimental details, see Vornov et al., J. Neurochem., Vol. 65, No. 4, pp. 1681-1691 (1995)). The results are provided below in Table V. Neuroprotective effect is expressed as EC50, the concentration of the compound, which is required to cause a 50% reduction in glutamate toxicity following an ischemic insult.
TABLE V Compound EC50 (nM) 4-[3-[[3-(2,4-dicarboxyphenoxy)-propyl]dithio]propoxy]- 2490 1,3-benzenedicarboxylic acid (19) 5-(3-mercaptopropoxy)-1,3-benzenedicarboxylic acid (36) 1240 5-[(hydroxyamino)-carbonyl]-1,3-benzenedicarboxylic 473 acid (39) 5-mercaptomethyl-1,3-benzenedicarboxylic acid (41) 172 4-(2-mercaptoethyl)-1,3-benzenedicarboxylic acid (22) 60 - A NAALADase inhibitor, Compound C, was added to ischemia cell cultures to determine its effect on TGF-β levels during stroke. The experimental data, set forth in
FIGS. 1 and 2 , show increased concentrations of TGF-β1 (FIG. 1 ) and TGF-β2 (FIG. 2 ) in ischemic cell cultures treated with Compound C. The results indicate that NAALADase inhibition promotes the release of endogenous TGF-β's from glial cells, which in turn provides neuroprotection for neighboring neurons. - TGF-β neutralizing antibodies were then added to the ischemic cell cultures.
FIG. 3 shows that the TGF-β neutralizing antibodies blocked the neuroprotective effect of Compound C in the in vitro ischemia model. By contrast,FIG. 4 shows that the addition of another growth factor antibody, FGF antibody, did not block the neuroprotective effect of Compound C. The results indicate that NAALADase inhibition specifically affects TGF-β levels during stroke. - The effect of TGF-β neutralizing antibodies on the neuroprotective effect of Compound C was also studied in rats following MCAO.
FIG. 6 shows that treatment of MCAO rats with Compound C caused a significant rise in TGF-β1 levels during both occlusion and reperfusion, as assessed by microdialysis. The results indicate that NAALADase inhibition provides neuroprotection, at least in part, by regulating endogenous TGF-β's. - Additionally,
FIG. 5 shows that TGF-β neutralizing antibodies significantly attenuated the neuroprotective effect of Compound C in vivo. One of ordinary skill in the art can appreciate that the regulation of TGF-β's by NAALADase inhibitors may have implications not only in stroke, but also in other diseases, disorders and conditions including, without limitation, neurological diseases, psychiatric diseases, demyelinating diseases, prostate cancer, inflammation, diabetes and angiogenesis. - Male Sprague-Dawley rats (200-225 g) were rendered diabetic by intravenous administration of streptozotocin (“STZ”, 70 mg/kg in phosphate buffered saline). Diabetic animals were divided into five groups: one group receiving Compound A (10 mg/kg or 1 mg/kg), Compound D (10 mg/kg or 1 mg/kg) or vehicle. Another group of animals (non-STZ treated) served as non-diabetic controls. Drug/vehicle treatment was started in
diabetic animals 45 days post-STZ administration. STZ-induced diabetic rats were tested for sensitivity to a heat source as soon as blood glucose levels rose to 320 mg/dl or above (30 days post STZ). The rats were then acclimated to the Hargreaves apparatus and thermal nociception was monitored using an infrared heat source directed into the dorsal surface of the hindpaw, and the time taken for the animal to remove its paw noted to the nearest 0.1 seconds (for detailed method, see Hargreaves et al., J. Biol. Chem. (1988) 263(36): 19392-7). The intensity of the beam source was adjusted such that the mean latency for control animals (non-STZ treated) was approximately 10 seconds. Each animal was tested 8 times and the mean difference score (between mean non-diabetic control latency and mean diabetic latency) are graphically presented inFIGS. 13A and 13B . Diabetic rats displayed a hyperalgesia (shorter response latency) compared to non-diabetic controls, starting 30 days post STZ treatment and progressively worsening in vehicle treated rats. This hyperalgesic response was completely reversed in diabetic rats receiving treatment with Compound D or A (10 mg/kg i.p. daily). Thus, the results show that NAALADase inhibition attenuates neuropathic pain. - Sciatic nerve ligation, consisting of 4 ligatures tied loosely around the sciatic nerve at 1 mm intervals proximal to the nerve trifurcation, was performed on rats. Following sciatic nerve ligation, the rats exhibited a thermal hyperalgesia and allodynia The rats were habituated to a Hargreaves apparatus. An infrared heat source was directed onto the dorsal surface of each rat's hindpaws and the time taken for the rat to withdraw its paws was noted. The difference in scores between the latency of the response for the paw on the operated side versus the paw on the unoperated control side was determined.
- Compound C
- Animals received Compound C (50 mg/kg i.p. daily) or vehicle, starting 10 days post surgery. Treatment with Compound C dramatically normalized the difference scores between the two paws compared to the continued hyperalgesic vehicle-treated controls. Normal (unoperated) rats had approximately equal latencies for both paws. This effect was significant starting at 11 days of drug treatment and persisted through to the end of the study (for 21 days of daily dosing). The difference scores are graphically presented in
FIG. 14 . The results show that NAALADase inhibition attenuates CCI-associated hyperalgesia. - Compounds D and A
- Male BB/W rats (BRI, Mass) spontaneously develop a cell mediated autoimmune destruction of pancreatic B cells, resulting in onset of insulin-dependent (Type I) diabetes (Awata and Guberski et al., Endocrinology 1995 December; 136(12): 5731-5). These rats have been characterized and shown to demonstrate neuropathies with accompanying neural deficits such as fiber loss and degeneration, changes which are correlative with those seen in peripheral nerve of human diabetic patients (Yagihasi, J. Peripher. Nerv. Syst. 1997; 2(2): 113-32). This renders them valuable for experimental trials of new compounds for future treatments of this major disorder. In the present study, Compound D and Compound A were examined for their ability to alter the progression of diabetic neuropathy. The rats received daily injection of Compound D or Compound A (10 mg/kg i.p.) or vehicle, starting at the onset of diabetes (hyperglycemia) and up to 6 months thereafter. Another group of non-diabetic rats also receiving vehicle were tested. All animals were continuously monitored for body weight, urine volume, blood sugar and glycated haemoglobin. In the first month of the study, all animals were tested for thermal nociception in a Hargreaves apparatus, weekly. After the first month this was done biweekly and then monthly. The testing consists of directing an infrared heat source onto the dorsal surface of the rat hindpaw and noting the time taken for the animal to remove its paw (for detailed method, see Hargreaves et al., J. Biol. Chem. 1988 Dec. 25; 263(36): 19392-7). Each animal was tested 8 times and the mean withdrawal latency noted.
- The results are graphically presented in
FIG. 17 . The results show that diabetic rats displayed a hyperalgesia (shorter response latency) compared to non-diabetic controls. Diabetic drug-treated rats (both Compound D and Compound A) displayed longer withdrawal latencies than diabetic vehicle-treated rats, starting after 4 weeks of treatment and persisting through the six months of treatment. - Nerve conduction velocity was also measured every two weeks through the first eight weeks of treatment and every month thereafter through to the six months of treatment. For detailed method, see De Koning et al., Peptides 1987 May-June; 8(3): 415-22. The results are graphically presented in
FIG. 18 . Diabetic animals generally showed a reduction in nerve conduction velocity compared to non-diabetic controls. However, diabetic animals receiving daily injections of NAALADase inhibitor (either Compound D or Compound A at a dose of 10 mg/kg) showed significantly less severe nerve conduction deficits than did the diabetic controls receiving vehicle treatment. This was apparent starting at 8 weeks of treatment and persisted to a similar degree through to the six month termination point of the study. Diabetic vehicles, on the other hand, showed a progressive deterioration in nerve conduction velocity from 6 to 16 weeks after start of vehicle administration which was maintained through to six months. - Motor and sensory nerve conduction velocity was also measured in STZ-diabetic animals after 4, 8 and 12 weeks of treatment. For detailed method, see De Koning et al., Peptides 1987 May-June; 8(3): 415-22. Briefly, stimulating needle electrodes were inserted close to the sciatic and tibial nerves with recording electrodes being placed subcutaneously over the distal foot muscles, in anesthetized rats. The results are graphically presented in
FIGS. 15A, 15B , 16A and 16B. Diabetic animals receiving vehicle showed a significant reduction in both motor and sensory nerve conduction compared to non-diabetic animals. Treatment with 10 mg/kg of Compound A daily for 4, 8 and 12 weeks all tended to improve (increase) both motor and sensory nerve conduction velocities, with a significant improvement being observed after 12 weeks and 8 weeks for motor and sensory nerve conduction velocity, respectively (FIGS. 15A and 15B ). A lower dose of Compound A tested (1 mg/kg) had similar effects. Treatment of animals with Compound D at either dose also increased both motor and sensory nerve conduction velocities above that of diabetic controls, significantly so after 12 weeks of treatment for the 10 mg/kg treatment group (FIGS. 16A and 16B ) and at the earlier time periods after treatment with the 1 mg/kg dose. Thus, the results show that NAALADase inhibition alters the progression of diabetic neuropathy. - A patient is suffering from any disease, disorder or condition mediated by NAALADase enzyme activity, including any of the diseases, disorders or conditions described above. The patient may then be administered an effective amount of a compound of formula I. It is expected that after such treatment, the patient would not suffer any significant injury due to, would be protected from further injury due to, or would recover from the disease, disorder or condition.
- All publications, patents and patent applications identified above are herein incorporated by reference, as though set forth herein in full.
- Those skilled in the art will recognize that the invention may be varied in many ways without departing from the invention's spirit and scope. Such variations are included within the scope of the following claims.
Claims (28)
1-7. (canceled)
8. A method for treating a glutamate abnormality in a mammal, comprising administering to said mammal an effective amount of a compound of formula I
a pharmaceutically acceptable equivalent, wherein:
X is —W-Z;
W is a bond or a linking group;
Z is a terminal group; and
Y is —COOH oriented meta or para relative to C-1.
9. The method of claim 8 , wherein the glutamate abnormality is compulsive disorder, stroke, demyelinating disease, schizophrenia, Parkinson's disease, ALS, anxiety, anxiety disorder, or memory impairment.
10. The method of claim 9 , wherein the glutamate abnormality is alcohol dependence.
11. The method of claim 9 , wherein the glutamate abnormality is nicotine dependence.
12. The method of claim 9 , wherein the glutamate abnormality is cocaine dependence.
13. A method for effecting a neuronal activity in a mammal, comprising administering to said mammal an effective amount of a compound of formula I
a pharmaceutically acceptable equivalent, wherein:
X is —W-Z;
W is a bond or a linking group;
Z is a terminal group; and
Y is —COOH oriented meta or para relative to C-1.
14. The method of claim 13 , wherein the neuronal activity is stimulation of damaged neurons, promotion of neuronal regeneration, prevention of neurodegeneration, or treatment of a neurological disorder.
15. The method of claim 14 , wherein the neuronal activity is treatment of a neurological disorder that is pain, neuropathy, traumatic brain injury, physical damage to spinal cord, stroke associated with brain damage, demyelinating disease, or a neurological disorder relating to neurodegeneration.
16. The method of claim 15 , wherein the method is treating peripheral neuropathy.
17. The method of claim 16 , wherein the peripheral neuropathy is caused by Type I or Type II diabetes, HIV, vitamins, or non-vitamin chemicals.
18. The method of claim 15 , wherein the method is treatment of neuropathic pain.
19. The method of claim 18 , wherein the neuropathic pain is caused by Type I or Type II diabetes, HIV, vitamins, or non-vitamin chemicals.
20. The method of claim 18 , wherein the compound of formula I is administered in combination with an effective amount of morphine.
21. The method of claim 15 , wherein the neuronal activity is treatment of Parkinson's disease or ALS.
22. A method for treating a prostate disease in a mammal, comprising administering to said mammal an effective amount of a compound of formula I
or a pharmaceutically acceptable equivalent, wherein:
X is —W-Z;
W is a bond or a linking group;
Z is a terminal group; and
Y is —COOH oriented meta or para relative to C-1.
23. The method of claim 22 , wherein the prostate disease is prostate cancer.
24. A method for treating cancer in a mammal, comprising administering to said mammal an effective amount of a compound of formula I
or a pharmaceutically acceptable equivalent, wherein:
X is —W-Z;
W is a bond or a linking group;
Z is a terminal group; and
Y is —COOH oriented meta or para relative to C-1.
25. The method of claim 24 , wherein the cancer is of the brain, kidney, or testis.
26. A method for inhibiting angiogenesis in a mammal, comprising administering to said mammal an effective amount of a compound of formula I
or a pharmaceutically acceptable equivalent, wherein:
X is —W-Z;
W is a bond or a linking group;
Z is a terminal group; and
Y is —COOH oriented meta or para relative to C-1.
27. A method for treating a TGF-β abnormality in a mammal, comprising administering to said mammal an effective amount of a compound of formula I
or a pharmaceutically acceptable equivalent, wherein:
X is —W-Z;
W is a bond or a linking group;
Z is a terminal group; and
Y is —COOH oriented meta or para relative to C-1.
28. A method for inhibiting NAALADase in a mammal, comprising administering to said mammal an effective amount of a compound of formula I
or a pharmaceutically acceptable equivalent, wherein:
X is —W-Z;
W is a bond or a linking group;
Z is a terminal group; and
Y is —COOH oriented meta or para relative to C-1.
29. A method for treating nervous insult in a mammal, comprising administering to said mammal an effective amount of a compound of formula I
or a pharmaceutically acceptable equivalent, wherein:
X is —W-Z;
W is a bond or a linking group;
Z is a terminal group; and
Y is —COOH oriented meta or para relative to C-1.
30. The method of claim 29 , wherein the nervous insult comprises a cognitive disorder.
31-38. (canceled)
39. A method for detecting a disease, disorder, or condition where NAALADase levels are altered, comprising:
(i) contacting a sample of bodily tissue or fluid with a compound of formula I,
or a pharmaceutically acceptable equivalent, wherein:
X is —W-Z;
W is a bond or a linking group;
Z is a terminal group; and
Y is —COOH oriented meta or para relative to C-1,
wherein said compound binds to any NAALADase in said sample; and
(ii) measuring the amount of any NAALADase bound to said sample, wherein the amount of NAALADase is diagnostic for said disease, disorder, or condition.
40. A method for detecting a disease, disorder, or condition where NAALADase levels are altered in an animal or a mammal, comprising:
(i) labeling a compound of formula I,
a pharmaceutically acceptable equivalent, with an imaging reagent, wherein:
X is —W-Z;
W is a bond or a linking group;
Z is a terminal group; and
Y is —COOH oriented meta or para relative to C-1,
(ii) administering to said animal or mammal an effective amount of the labeled compound;
(i) allowing said labeled compound to localize and bind to NAALADase present in said animal or mammal; and
(ii) measuring the amount of NAALADase bound to said labeled compound, wherein the amount of NAALADase is diagnostic for said disease, disorder or condition.
41. A diagnostic kit for detecting a disease, disorder or condition where NAALADase levels are altered, comprising a compound of formula I, or a pharmaceutically acceptable equivalent, labeled with a marker,
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US11/051,188 US20050171065A1 (en) | 2000-05-30 | 2005-02-07 | Benzenedicarboxylic acid derivatives |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US20740200P | 2000-05-30 | 2000-05-30 | |
US09/866,758 US6452044B2 (en) | 2000-05-30 | 2001-05-30 | Benzenedicarboxylic acid derivatives |
US10/176,046 US6852750B2 (en) | 2000-05-30 | 2002-06-21 | Benzenedicarboxylic acid derivatives |
US11/051,188 US20050171065A1 (en) | 2000-05-30 | 2005-02-07 | Benzenedicarboxylic acid derivatives |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US10/176,046 Division US6852750B2 (en) | 2000-05-30 | 2002-06-21 | Benzenedicarboxylic acid derivatives |
Publications (1)
Publication Number | Publication Date |
---|---|
US20050171065A1 true US20050171065A1 (en) | 2005-08-04 |
Family
ID=22770402
Family Applications (3)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US09/866,758 Expired - Fee Related US6452044B2 (en) | 2000-05-30 | 2001-05-30 | Benzenedicarboxylic acid derivatives |
US10/176,046 Expired - Fee Related US6852750B2 (en) | 2000-05-30 | 2002-06-21 | Benzenedicarboxylic acid derivatives |
US11/051,188 Abandoned US20050171065A1 (en) | 2000-05-30 | 2005-02-07 | Benzenedicarboxylic acid derivatives |
Family Applications Before (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US09/866,758 Expired - Fee Related US6452044B2 (en) | 2000-05-30 | 2001-05-30 | Benzenedicarboxylic acid derivatives |
US10/176,046 Expired - Fee Related US6852750B2 (en) | 2000-05-30 | 2002-06-21 | Benzenedicarboxylic acid derivatives |
Country Status (3)
Country | Link |
---|---|
US (3) | US6452044B2 (en) |
AU (1) | AU2001265111A1 (en) |
WO (1) | WO2001092273A2 (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2012082903A2 (en) * | 2010-12-14 | 2012-06-21 | The Johns Hopkins University | Treatment of cognitive impairment in a subject with a neurological autoimmune disease |
Families Citing this family (23)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7105159B1 (en) | 1992-11-05 | 2006-09-12 | Sloan-Kettering Institute For Cancer Research | Antibodies to prostate-specific membrane antigen |
US7070782B1 (en) * | 1992-11-05 | 2006-07-04 | Sloan-Kettering Institute For Cancer Research | Prostate-specific membrane antigen |
US6953668B1 (en) | 1992-11-05 | 2005-10-11 | Sloan-Kettering Institute For Cancer Research | Prostate-specific membrane antigen |
US6569432B1 (en) * | 1995-02-24 | 2003-05-27 | Sloan-Kettering Institute For Cancer Research | Prostate-specific membrane antigen and uses thereof |
CA2212846A1 (en) | 1995-02-24 | 1996-08-29 | Sloan-Kettering Institute For Cancer Research | Prostate-specific membrane antigen and uses thereof |
US20040253246A1 (en) * | 1996-02-23 | 2004-12-16 | Israeli Ron S. | Prostate-specific membrane antigen and uses thereof |
WO2001092273A2 (en) * | 2000-05-30 | 2001-12-06 | Guilford Pharmaceuticals Inc. | Benzenedicarboxylic acid derivatives |
US20020013295A1 (en) * | 2000-05-30 | 2002-01-31 | Slusher Barbara S. | Naaladase inhibitors for treating amyotrophic lateral sclerosis |
JP4234430B2 (en) | 2001-01-17 | 2009-03-04 | エムジーアイ ジーピー インコーポレイティッド | NAALADase inhibitors containing thiols |
EP1355640A1 (en) | 2001-01-23 | 2003-10-29 | Neurosearch A/S | Use of non-competitive and selective glur5 antagonists as glutamate receptor modulating compounds |
DE60214134T2 (en) * | 2001-02-07 | 2007-07-19 | Beth Israel Deaconess Medical Center, Boston | MODIFIED PSMA LIGANDS AND THEIR USE |
EP1392648A1 (en) | 2001-05-11 | 2004-03-03 | Guilford Pharmaceuticals Inc. | Hydroxamic acids and acyl hydroxamines as naaladase inhibitors |
EP2025666A3 (en) | 2001-05-30 | 2010-03-31 | Eisai Inc. | Thiolalkyl benzoic acid derivatives |
IL161267A0 (en) * | 2001-10-05 | 2004-09-27 | Combinatorx Inc | Combinations for the treatment of immunoinflammatory disorders |
AU2002357003A1 (en) | 2001-12-28 | 2003-07-24 | Guilford Pharmaceuticals Inc. | Indoles as naaladase inhibitors |
US7125907B2 (en) * | 2003-03-03 | 2006-10-24 | Guilford Pharmaceuticals Inc. | Thiolactones |
US20040186081A1 (en) * | 2003-03-03 | 2004-09-23 | Guilford Pharmaceuticals Inc. | Naaladase inhibitors for treating opioid tolerance |
US6795706B1 (en) * | 2003-04-10 | 2004-09-21 | Benq Corporation | Efficient direct call database management for mobile devices with limited non-volatile memory |
GB2404855A (en) * | 2003-07-07 | 2005-02-16 | Pantherix Ltd | Arylcarboxylic acid derivatives and their therapeutic use |
US7863301B2 (en) | 2003-08-21 | 2011-01-04 | Wisconsin Alumni Research Foundation | Potentiators of insulin secretion |
EP1998760A2 (en) * | 2006-03-30 | 2008-12-10 | James E. Summerton | Non peptidic molecules for detecting and treating tumors |
CA2682567A1 (en) * | 2007-03-30 | 2008-10-09 | James E. Summerton | Non-peptidic molecules for detecting and treating tumors |
US9067878B2 (en) * | 2010-06-22 | 2015-06-30 | Xerox Corporation | Organogel compositions comprising alkylated aromatic acids |
Citations (37)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US644637A (en) * | 1899-11-20 | 1900-03-06 | James R Reid | Filtering material. |
US688907A (en) * | 1899-12-11 | 1901-12-17 | Wallmann Engine Company | Internal-combustion engine. |
US4250182A (en) * | 1972-02-24 | 1981-02-10 | Burroughs Wellcome Co. | Pharmaceutical composition containing acridone compounds and method of using same |
US4863636A (en) * | 1988-02-12 | 1989-09-05 | American Cyanamid Company | Substituted N-hydroxyphthalimides and their use as detergent additives |
US5498784A (en) * | 1995-02-21 | 1996-03-12 | The United States Of America As Represented By The Secretary Of The Air Force | Phosphonic acid-pendent benzoxazole copolymers |
US5672592A (en) * | 1996-06-17 | 1997-09-30 | Guilford Pharmaceuticals Inc. | Certain phosphonomethyl-pentanedioic acid derivatives thereof |
US5795877A (en) * | 1996-12-31 | 1998-08-18 | Guilford Pharmaceuticals Inc. | Inhibitors of NAALADase enzyme activity |
US5804602A (en) * | 1996-06-17 | 1998-09-08 | Guilford Pharmaceuticals Inc. | Methods of cancer treatment using naaladase inhibitors |
US5807688A (en) * | 1995-05-27 | 1998-09-15 | Zeneca Limited | Catalytic antibodies for carbamate activation by a non-spontaneous reaction mechanism |
US5824662A (en) * | 1996-09-27 | 1998-10-20 | Guilford Pharmaceuticals Inc. | Treatment of global and focal ischemia using naaladase inhibitors |
US5863536A (en) * | 1996-12-31 | 1999-01-26 | Guilford Pharmaceuticals Inc. | Phosphoramidate derivatives |
US5902817A (en) * | 1997-04-09 | 1999-05-11 | Guilford Pharmaceuticals Inc. | Certain sulfoxide and sulfone derivatives |
US5962521A (en) * | 1997-04-04 | 1999-10-05 | Guilford Pharmaceuticals Inc. | Hydroxamic acid derivatives |
US5977090A (en) * | 1996-09-27 | 1999-11-02 | Guilford Pharmaceuticals Inc. | Pharmaceutical compositions and methods of treating compulsive disorders using NAALADase inhibitors |
US5981209A (en) * | 1997-12-04 | 1999-11-09 | Guilford Pharmaceuticals Inc. | Use of NAALADase activity to identify prostate cancer and benign prostatic hyperplasia |
US6011021A (en) * | 1996-06-17 | 2000-01-04 | Guilford Pharmaceuticals Inc. | Methods of cancer treatment using naaladase inhibitors |
US6017903A (en) * | 1996-09-27 | 2000-01-25 | Guilford Pharmaceuticals Inc. | Pharmaceutical compositions and methods of treating a glutamate abnormality and effecting a neuronal activity in an animal using NAALADase inhibitors |
US6025344A (en) * | 1996-06-17 | 2000-02-15 | Guilford Pharmaceuticals Inc. | Certain dioic acid derivatives useful as NAALADase inhibitors |
US6025345A (en) * | 1996-06-17 | 2000-02-15 | Guilford Pharmaceuticals Inc. | Inhibitors of NAALADase enzyme activity |
US6028216A (en) * | 1997-12-31 | 2000-02-22 | Guilford Pharmaceuticals Inc. | Asymmetric syntheses and intermediates for preparing enantiomer-enriched hydroxyphosphinyl derivatives |
US6046180A (en) * | 1996-06-17 | 2000-04-04 | Guilford Pharmaceuticals Inc. | NAALADase inhibitors |
US6054444A (en) * | 1997-04-24 | 2000-04-25 | Guilford Pharmaceuticals Inc. | Phosphonic acid derivatives |
US6071965A (en) * | 1996-06-17 | 2000-06-06 | Guilford Pharmaceuticals Inc. | Phosphinic alkanoic acid derivatives |
US6121252A (en) * | 1998-03-30 | 2000-09-19 | Guilford Pharmaceuticals Inc. | Phosphinic acid derivatives |
US6228888B1 (en) * | 1999-07-01 | 2001-05-08 | Guilford Pharmaceuticals Inc. | Methods for treating anxiety, anxiety disorders and memory impairment using naaladase inhibitors |
US6313159B1 (en) * | 1999-08-20 | 2001-11-06 | Guilford Pharmaceuticals Inc. | Metabotropic glutamate receptor ligand derivatives as naaladase inhibitors |
US6348464B1 (en) * | 1999-11-12 | 2002-02-19 | Guilford Pharmaceuticals, Inc. | Pyrrolecarbonylimino derivatives as naaladase inhibitors |
US6372726B1 (en) * | 1996-06-17 | 2002-04-16 | Guilford Pharmaceuticals Inc. | Methods of cancer treatment using NAALADase inhibitors |
US6384022B1 (en) * | 1996-06-17 | 2002-05-07 | Guilford Pharmaceuticals Inc. | Prodrugs of NAALAdase inhibitors |
US6395718B1 (en) * | 1998-07-06 | 2002-05-28 | Guilford Pharmaceuticals Inc. | Pharmaceutical compositions and methods of inhibiting angiogenesis using naaladase inhibitors |
US6413948B1 (en) * | 1996-09-27 | 2002-07-02 | Guilford Pharmaceuticals Inc. | Pharmaceutical compositions and methods of effecting a neuronal activity in an animal using naaladase inhibitors |
US6444657B1 (en) * | 1998-12-31 | 2002-09-03 | Guilford Pharmaceuticals Inc. | Methods for treating certain diseases using naaladase inhibitors |
US6452044B2 (en) * | 2000-05-30 | 2002-09-17 | Guilford Pharmaceuticals Inc. | Benzenedicarboxylic acid derivatives |
US6458775B1 (en) * | 1998-07-06 | 2002-10-01 | Guilford Pharmaceutical Inc. | NAALADase inhibitors useful as pharmaceutical compounds and compositions |
US6565609B1 (en) * | 1999-06-15 | 2003-05-20 | Microsoft Corporation | Translating data into HTML while retaining formatting and functionality for returning the translated data to a parent application |
US6740777B2 (en) * | 2001-05-30 | 2004-05-25 | Guilford Pharmaceuticals Inc. | Thiolalkyl benzoic acid derivatives |
US6884907B2 (en) * | 2001-05-11 | 2005-04-26 | Guilford Pharmaceuticals Inc. | Hydroxamic acids and acyl hydroxamines as naaladase inhibitors |
Family Cites Families (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
NL6606892A (en) * | 1966-05-18 | 1966-07-25 | ||
GB1424074A (en) * | 1973-06-22 | 1976-02-04 | Leo Pharm Prod Ltd | Methylsulphonyl-benzoic acid derivatives |
GB1434405A (en) * | 1973-09-06 | 1976-05-05 | Leo Pharm Prod Ltd | Phenyl-benzoic acid derivatives |
CS162594B1 (en) * | 1974-04-25 | 1975-07-15 | ||
JPH02204754A (en) | 1989-02-02 | 1990-08-14 | Fuji Photo Film Co Ltd | Liquid developer for electrostatic photography |
JPH02208666A (en) | 1989-02-08 | 1990-08-20 | Fuji Photo Film Co Ltd | Liquid developer for electrostatic photography |
US5880309A (en) | 1997-01-28 | 1999-03-09 | Nissan Chemical Industries, Ltd. | Phenylphosphonic acid derivative and production process therefor |
EP0994707A4 (en) * | 1997-05-27 | 2001-11-14 | Guilford Pharm Inc | Inhibitors of naaladase enzyme activity |
JP4132327B2 (en) | 1997-12-25 | 2008-08-13 | 日産化学工業株式会社 | Phenylenebis (phosphonic acid) compound and method for producing the same |
JP2000095788A (en) | 1998-09-22 | 2000-04-04 | Nissan Chem Ind Ltd | Production of phenylphosphonic acid |
JP2000159984A (en) | 1998-11-30 | 2000-06-13 | Toray Ind Inc | Polyester composition and its production |
-
2001
- 2001-05-29 WO PCT/US2001/017309 patent/WO2001092273A2/en active Application Filing
- 2001-05-29 AU AU2001265111A patent/AU2001265111A1/en not_active Abandoned
- 2001-05-30 US US09/866,758 patent/US6452044B2/en not_active Expired - Fee Related
-
2002
- 2002-06-21 US US10/176,046 patent/US6852750B2/en not_active Expired - Fee Related
-
2005
- 2005-02-07 US US11/051,188 patent/US20050171065A1/en not_active Abandoned
Patent Citations (46)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US644637A (en) * | 1899-11-20 | 1900-03-06 | James R Reid | Filtering material. |
US688907A (en) * | 1899-12-11 | 1901-12-17 | Wallmann Engine Company | Internal-combustion engine. |
US4250182A (en) * | 1972-02-24 | 1981-02-10 | Burroughs Wellcome Co. | Pharmaceutical composition containing acridone compounds and method of using same |
US4863636A (en) * | 1988-02-12 | 1989-09-05 | American Cyanamid Company | Substituted N-hydroxyphthalimides and their use as detergent additives |
US5498784A (en) * | 1995-02-21 | 1996-03-12 | The United States Of America As Represented By The Secretary Of The Air Force | Phosphonic acid-pendent benzoxazole copolymers |
US5807688A (en) * | 1995-05-27 | 1998-09-15 | Zeneca Limited | Catalytic antibodies for carbamate activation by a non-spontaneous reaction mechanism |
US6025345A (en) * | 1996-06-17 | 2000-02-15 | Guilford Pharmaceuticals Inc. | Inhibitors of NAALADase enzyme activity |
US6011021A (en) * | 1996-06-17 | 2000-01-04 | Guilford Pharmaceuticals Inc. | Methods of cancer treatment using naaladase inhibitors |
US6372726B1 (en) * | 1996-06-17 | 2002-04-16 | Guilford Pharmaceuticals Inc. | Methods of cancer treatment using NAALADase inhibitors |
US6384022B1 (en) * | 1996-06-17 | 2002-05-07 | Guilford Pharmaceuticals Inc. | Prodrugs of NAALAdase inhibitors |
US6071965A (en) * | 1996-06-17 | 2000-06-06 | Guilford Pharmaceuticals Inc. | Phosphinic alkanoic acid derivatives |
US5880112A (en) * | 1996-06-17 | 1999-03-09 | Guilford Pharmaceuticals Inc. | Naaladase inhibitors |
US6046180A (en) * | 1996-06-17 | 2000-04-04 | Guilford Pharmaceuticals Inc. | NAALADase inhibitors |
US5672592A (en) * | 1996-06-17 | 1997-09-30 | Guilford Pharmaceuticals Inc. | Certain phosphonomethyl-pentanedioic acid derivatives thereof |
US5968915A (en) * | 1996-06-17 | 1999-10-19 | Guilford Pharmaceuticals Inc. | Naaladase inhibitors |
US6025344A (en) * | 1996-06-17 | 2000-02-15 | Guilford Pharmaceuticals Inc. | Certain dioic acid derivatives useful as NAALADase inhibitors |
US5804602A (en) * | 1996-06-17 | 1998-09-08 | Guilford Pharmaceuticals Inc. | Methods of cancer treatment using naaladase inhibitors |
US5985855A (en) * | 1996-09-27 | 1999-11-16 | Guilford Pharmaceuticals Inc. | Treatment of global and focal ischemia using NAALADase inhibitors |
US6004946A (en) * | 1996-09-27 | 1999-12-21 | Guilford Pharmaceuticals Inc. | Treatment of global and focal ischemia using naaladase inhibitors |
US6017903A (en) * | 1996-09-27 | 2000-01-25 | Guilford Pharmaceuticals Inc. | Pharmaceutical compositions and methods of treating a glutamate abnormality and effecting a neuronal activity in an animal using NAALADase inhibitors |
US5977090A (en) * | 1996-09-27 | 1999-11-02 | Guilford Pharmaceuticals Inc. | Pharmaceutical compositions and methods of treating compulsive disorders using NAALADase inhibitors |
US6413948B1 (en) * | 1996-09-27 | 2002-07-02 | Guilford Pharmaceuticals Inc. | Pharmaceutical compositions and methods of effecting a neuronal activity in an animal using naaladase inhibitors |
US5824662A (en) * | 1996-09-27 | 1998-10-20 | Guilford Pharmaceuticals Inc. | Treatment of global and focal ischemia using naaladase inhibitors |
US5863536A (en) * | 1996-12-31 | 1999-01-26 | Guilford Pharmaceuticals Inc. | Phosphoramidate derivatives |
US5795877A (en) * | 1996-12-31 | 1998-08-18 | Guilford Pharmaceuticals Inc. | Inhibitors of NAALADase enzyme activity |
US5962521A (en) * | 1997-04-04 | 1999-10-05 | Guilford Pharmaceuticals Inc. | Hydroxamic acid derivatives |
US6271245B1 (en) * | 1997-04-04 | 2001-08-07 | Guilford Pharmaceuticals, Inc. | Hydroxamic acid derivatives |
US5902817A (en) * | 1997-04-09 | 1999-05-11 | Guilford Pharmaceuticals Inc. | Certain sulfoxide and sulfone derivatives |
US6288046B1 (en) * | 1997-04-24 | 2001-09-11 | Guilford Pharmaceuticals Inc. | Phosphonic acid derivatives |
US6054444A (en) * | 1997-04-24 | 2000-04-25 | Guilford Pharmaceuticals Inc. | Phosphonic acid derivatives |
US5981209A (en) * | 1997-12-04 | 1999-11-09 | Guilford Pharmaceuticals Inc. | Use of NAALADase activity to identify prostate cancer and benign prostatic hyperplasia |
US6028216A (en) * | 1997-12-31 | 2000-02-22 | Guilford Pharmaceuticals Inc. | Asymmetric syntheses and intermediates for preparing enantiomer-enriched hydroxyphosphinyl derivatives |
US6121252A (en) * | 1998-03-30 | 2000-09-19 | Guilford Pharmaceuticals Inc. | Phosphinic acid derivatives |
US6458775B1 (en) * | 1998-07-06 | 2002-10-01 | Guilford Pharmaceutical Inc. | NAALADase inhibitors useful as pharmaceutical compounds and compositions |
US6395718B1 (en) * | 1998-07-06 | 2002-05-28 | Guilford Pharmaceuticals Inc. | Pharmaceutical compositions and methods of inhibiting angiogenesis using naaladase inhibitors |
US6444657B1 (en) * | 1998-12-31 | 2002-09-03 | Guilford Pharmaceuticals Inc. | Methods for treating certain diseases using naaladase inhibitors |
US6565609B1 (en) * | 1999-06-15 | 2003-05-20 | Microsoft Corporation | Translating data into HTML while retaining formatting and functionality for returning the translated data to a parent application |
US6376478B1 (en) * | 1999-07-01 | 2002-04-23 | Guilford Pharmaceuticals Inc. | Pharmaceutical compositions and methods for treating anxiety, anxiety disorders and memory impairment using naaladase inhibitors |
US6228888B1 (en) * | 1999-07-01 | 2001-05-08 | Guilford Pharmaceuticals Inc. | Methods for treating anxiety, anxiety disorders and memory impairment using naaladase inhibitors |
US6313159B1 (en) * | 1999-08-20 | 2001-11-06 | Guilford Pharmaceuticals Inc. | Metabotropic glutamate receptor ligand derivatives as naaladase inhibitors |
US6348464B1 (en) * | 1999-11-12 | 2002-02-19 | Guilford Pharmaceuticals, Inc. | Pyrrolecarbonylimino derivatives as naaladase inhibitors |
US6452044B2 (en) * | 2000-05-30 | 2002-09-17 | Guilford Pharmaceuticals Inc. | Benzenedicarboxylic acid derivatives |
US6852750B2 (en) * | 2000-05-30 | 2005-02-08 | Guilford Pharmaceuticals, Inc. | Benzenedicarboxylic acid derivatives |
US6884907B2 (en) * | 2001-05-11 | 2005-04-26 | Guilford Pharmaceuticals Inc. | Hydroxamic acids and acyl hydroxamines as naaladase inhibitors |
US6740777B2 (en) * | 2001-05-30 | 2004-05-25 | Guilford Pharmaceuticals Inc. | Thiolalkyl benzoic acid derivatives |
US20040198824A1 (en) * | 2001-05-30 | 2004-10-07 | Guilford Pharmaceuticals Inc. | Thioalkyl benzoic acid derivatives |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2012082903A2 (en) * | 2010-12-14 | 2012-06-21 | The Johns Hopkins University | Treatment of cognitive impairment in a subject with a neurological autoimmune disease |
WO2012082903A3 (en) * | 2010-12-14 | 2012-10-26 | The Johns Hopkins University | Treatment of cognitive impairment in a subject with a neurological autoimmune disease |
US9737552B2 (en) | 2010-12-14 | 2017-08-22 | The Johns Hopkins University | Treatment of cognitive impairment in a subject with a neurological autoimmune disease |
Also Published As
Publication number | Publication date |
---|---|
WO2001092273A3 (en) | 2002-07-25 |
US20030083505A1 (en) | 2003-05-01 |
US20020019430A1 (en) | 2002-02-14 |
WO2001092273A2 (en) | 2001-12-06 |
AU2001265111A1 (en) | 2001-12-11 |
US6452044B2 (en) | 2002-09-17 |
US6852750B2 (en) | 2005-02-08 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US20050171065A1 (en) | Benzenedicarboxylic acid derivatives | |
US7148250B2 (en) | Indoles as NAALADase inhibitors | |
US20060135812A1 (en) | Thiol-based NAALADase inhibitors | |
US20060009525A1 (en) | Hydroxamic acids and acyl hydroxamines as NAALADase inhibitors | |
AU2002245271A1 (en) | Thiol-based NAALADase inhibitors | |
US6348464B1 (en) | Pyrrolecarbonylimino derivatives as naaladase inhibitors | |
AU2002256505A1 (en) | Hydroxamic acids and acyl hydroxamines as naaladase inhibitors | |
US7138543B2 (en) | Thiolalkyl benzoic acid derivatives | |
AU2002310202A1 (en) | Thiolalkyl benzoic acid derivatives |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
STCB | Information on status: application discontinuation |
Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION |