CN108289882B - Crmp2 sumo化抑制剂以及其用途 - Google Patents
Crmp2 sumo化抑制剂以及其用途 Download PDFInfo
- Publication number
- CN108289882B CN108289882B CN201680068806.1A CN201680068806A CN108289882B CN 108289882 B CN108289882 B CN 108289882B CN 201680068806 A CN201680068806 A CN 201680068806A CN 108289882 B CN108289882 B CN 108289882B
- Authority
- CN
- China
- Prior art keywords
- compounds
- compound
- crmp2
- acid
- pain
- 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.)
- Active
Links
- 102100024426 Dihydropyrimidinase-related protein 2 Human genes 0.000 title claims description 23
- 101001053503 Homo sapiens Dihydropyrimidinase-related protein 2 Proteins 0.000 title claims description 23
- 239000003112 inhibitor Substances 0.000 title description 7
- 150000001875 compounds Chemical class 0.000 claims abstract description 131
- 101000654386 Homo sapiens Sodium channel protein type 9 subunit alpha Proteins 0.000 claims abstract description 21
- 102100031367 Sodium channel protein type 9 subunit alpha Human genes 0.000 claims abstract description 19
- -1 small molecule compound Chemical class 0.000 claims description 60
- 208000002193 Pain Diseases 0.000 claims description 38
- 230000036407 pain Effects 0.000 claims description 28
- 239000001257 hydrogen Substances 0.000 claims description 12
- 229910052739 hydrogen Inorganic materials 0.000 claims description 12
- 230000002401 inhibitory effect Effects 0.000 claims description 10
- 239000003795 chemical substances by application Substances 0.000 claims description 9
- 229910052760 oxygen Inorganic materials 0.000 claims description 8
- 230000000694 effects Effects 0.000 claims description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 6
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 3
- 239000011737 fluorine Substances 0.000 claims description 3
- 229910052731 fluorine Inorganic materials 0.000 claims description 3
- 238000003032 molecular docking Methods 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 238000007069 methylation reaction Methods 0.000 claims description 2
- 150000003384 small molecules Chemical group 0.000 claims description 2
- 125000000539 amino acid group Chemical group 0.000 claims 2
- 230000011987 methylation Effects 0.000 claims 1
- 210000004027 cell Anatomy 0.000 abstract description 45
- 238000000034 method Methods 0.000 abstract description 37
- 102000004169 proteins and genes Human genes 0.000 abstract description 11
- 108090000623 proteins and genes Proteins 0.000 abstract description 11
- 230000004913 activation Effects 0.000 abstract description 10
- 230000010741 sumoylation Effects 0.000 abstract description 3
- 230000008050 pain signaling Effects 0.000 abstract description 2
- 230000029936 alkylation Effects 0.000 abstract 1
- 238000005804 alkylation reaction Methods 0.000 abstract 1
- 239000000203 mixture Substances 0.000 description 43
- 230000015572 biosynthetic process Effects 0.000 description 34
- 238000003786 synthesis reaction Methods 0.000 description 32
- 239000007787 solid Substances 0.000 description 31
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 30
- 239000000243 solution Substances 0.000 description 30
- 210000003594 spinal ganglia Anatomy 0.000 description 28
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 26
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 26
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 24
- 238000005160 1H NMR spectroscopy Methods 0.000 description 20
- 238000000589 high-performance liquid chromatography-mass spectrometry Methods 0.000 description 18
- 102000002669 Small Ubiquitin-Related Modifier Proteins Human genes 0.000 description 17
- 108010043401 Small Ubiquitin-Related Modifier Proteins Proteins 0.000 description 17
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 17
- 238000009472 formulation Methods 0.000 description 17
- 125000001424 substituent group Chemical group 0.000 description 17
- 241000700159 Rattus Species 0.000 description 16
- 239000004480 active ingredient Substances 0.000 description 16
- 201000010099 disease Diseases 0.000 description 16
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 16
- 239000000047 product Substances 0.000 description 16
- 150000003839 salts Chemical class 0.000 description 16
- 229910052757 nitrogen Inorganic materials 0.000 description 15
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 13
- 239000000843 powder Substances 0.000 description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- 239000000370 acceptor Substances 0.000 description 12
- 210000002569 neuron Anatomy 0.000 description 12
- 239000008194 pharmaceutical composition Substances 0.000 description 12
- 238000003756 stirring Methods 0.000 description 12
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 12
- 238000006243 chemical reaction Methods 0.000 description 11
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 11
- 239000011734 sodium Substances 0.000 description 11
- 125000005605 benzo group Chemical group 0.000 description 10
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 10
- 238000002474 experimental method Methods 0.000 description 10
- 230000002779 inactivation Effects 0.000 description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 125000000217 alkyl group Chemical group 0.000 description 9
- 239000011324 bead Substances 0.000 description 9
- 125000000623 heterocyclic group Chemical group 0.000 description 9
- 235000018102 proteins Nutrition 0.000 description 9
- 239000003826 tablet Substances 0.000 description 9
- 238000001890 transfection Methods 0.000 description 9
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 8
- MWAYRGBWOVHDDZ-UHFFFAOYSA-N Ethyl vanillate Chemical compound CCOC(=O)C1=CC=C(O)C(OC)=C1 MWAYRGBWOVHDDZ-UHFFFAOYSA-N 0.000 description 8
- FVECELJHCSPHKY-WTFKENEKSA-N Veratrine (amorphous) Chemical compound C1=C(OC)C(OC)=CC=C1C(=O)O[C@@H]1[C@]2(O)O[C@@]34C[C@@]5(O)[C@H](CN6[C@@H](CC[C@H](C)C6)[C@@]6(C)O)[C@]6(O)[C@@H](O)C[C@@]5(O)[C@@H]4CC[C@H]2[C@]3(C)CC1 FVECELJHCSPHKY-WTFKENEKSA-N 0.000 description 8
- 239000002775 capsule Substances 0.000 description 8
- UWGBIKPRXRSRNM-UHFFFAOYSA-N cevadine Natural products CC=C(C)/C(=O)OC1CCC2(C)C3CCC4C5(O)CC(O)C6(O)C(CN7CC(C)CCC7C6(C)O)C5(O)CC24OCC13O UWGBIKPRXRSRNM-UHFFFAOYSA-N 0.000 description 8
- 239000002552 dosage form Substances 0.000 description 8
- 239000000651 prodrug Substances 0.000 description 8
- 229940002612 prodrug Drugs 0.000 description 8
- 125000006239 protecting group Chemical group 0.000 description 8
- 238000012360 testing method Methods 0.000 description 8
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 7
- 108091006146 Channels Proteins 0.000 description 7
- 208000000094 Chronic Pain Diseases 0.000 description 7
- 239000011541 reaction mixture Substances 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- CGLIQMSZLNFKAV-UHFFFAOYSA-N 3-methoxy-4-[[3-(trifluoromethyl)phenyl]methoxy]benzoic acid Chemical compound COC=1C=C(C(=O)O)C=CC=1OCC1=CC(=CC=C1)C(F)(F)F CGLIQMSZLNFKAV-UHFFFAOYSA-N 0.000 description 6
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 6
- 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 6
- 208000028389 Nerve injury Diseases 0.000 description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 239000012043 crude product Substances 0.000 description 6
- 239000003085 diluting agent Substances 0.000 description 6
- 125000001188 haloalkyl group Chemical group 0.000 description 6
- 230000008764 nerve damage Effects 0.000 description 6
- 239000000546 pharmaceutical excipient Substances 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 6
- 239000002244 precipitate Substances 0.000 description 6
- 229910052708 sodium Inorganic materials 0.000 description 6
- MOZNZNKHRXRLLF-UHFFFAOYSA-N 4-(4-methylpiperazin-1-yl)aniline Chemical compound C1CN(C)CCN1C1=CC=C(N)C=C1 MOZNZNKHRXRLLF-UHFFFAOYSA-N 0.000 description 5
- HRWITLKRRXAYJL-UHFFFAOYSA-N COC=1C=C(C(=O)Cl)C=CC=1OCC1=CC(=CC=C1)C(F)(F)F Chemical compound COC=1C=C(C(=O)Cl)C=CC=1OCC1=CC(=CC=C1)C(F)(F)F HRWITLKRRXAYJL-UHFFFAOYSA-N 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 5
- 238000004458 analytical method Methods 0.000 description 5
- 125000003118 aryl group Chemical group 0.000 description 5
- 125000004432 carbon atom Chemical group C* 0.000 description 5
- 239000000969 carrier Substances 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 239000003937 drug carrier Substances 0.000 description 5
- 239000000839 emulsion Substances 0.000 description 5
- 230000006870 function Effects 0.000 description 5
- 125000004404 heteroalkyl group Chemical group 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 208000004296 neuralgia Diseases 0.000 description 5
- 208000021722 neuropathic pain Diseases 0.000 description 5
- 239000013612 plasmid Substances 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- 230000004044 response Effects 0.000 description 5
- 229920006395 saturated elastomer Polymers 0.000 description 5
- 210000003491 skin Anatomy 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- 230000001225 therapeutic effect Effects 0.000 description 5
- 238000011282 treatment Methods 0.000 description 5
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 4
- 238000005481 NMR spectroscopy Methods 0.000 description 4
- 125000003545 alkoxy group Chemical group 0.000 description 4
- 125000002947 alkylene group Chemical group 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 238000003556 assay Methods 0.000 description 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- 239000000460 chlorine Substances 0.000 description 4
- 235000019439 ethyl acetate Nutrition 0.000 description 4
- 210000002683 foot Anatomy 0.000 description 4
- 150000002430 hydrocarbons Chemical group 0.000 description 4
- 239000010410 layer Substances 0.000 description 4
- 125000005647 linker group Chemical group 0.000 description 4
- 239000007937 lozenge Substances 0.000 description 4
- 230000004048 modification Effects 0.000 description 4
- 238000012986 modification Methods 0.000 description 4
- 210000003205 muscle Anatomy 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- 239000001301 oxygen Substances 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- 125000006413 ring segment Chemical group 0.000 description 4
- 238000012216 screening Methods 0.000 description 4
- 239000003381 stabilizer Substances 0.000 description 4
- 238000007920 subcutaneous administration Methods 0.000 description 4
- 229910052717 sulfur Inorganic materials 0.000 description 4
- 239000000375 suspending agent Substances 0.000 description 4
- 238000013268 sustained release Methods 0.000 description 4
- 208000024891 symptom Diseases 0.000 description 4
- 238000002560 therapeutic procedure Methods 0.000 description 4
- 239000002562 thickening agent Substances 0.000 description 4
- 239000003981 vehicle Substances 0.000 description 4
- GBMPUGYTXRHCKB-UHFFFAOYSA-N 3-fluoro-4-(2-morpholin-4-ylethoxy)benzoic acid Chemical compound FC=1C=C(C(=O)O)C=CC=1OCCN1CCOCC1 GBMPUGYTXRHCKB-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- QEBXRHWELZTZOA-UHFFFAOYSA-N COC=1C=C(C(=O)Cl)C=CC=1OCC1=CC=C(C=C1)OC(F)(F)F Chemical compound COC=1C=C(C(=O)Cl)C=CC=1OCC1=CC=C(C=C1)OC(F)(F)F QEBXRHWELZTZOA-UHFFFAOYSA-N 0.000 description 3
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 3
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 3
- 108010010803 Gelatin Proteins 0.000 description 3
- 208000004454 Hyperalgesia Diseases 0.000 description 3
- 206010020751 Hypersensitivity Diseases 0.000 description 3
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 3
- 240000007472 Leucaena leucocephala Species 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- 241000124008 Mammalia Species 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 3
- 239000007832 Na2SO4 Substances 0.000 description 3
- 102000051619 SUMO-1 Human genes 0.000 description 3
- 108700038981 SUMO-1 Proteins 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 3
- 208000005298 acute pain Diseases 0.000 description 3
- 208000026935 allergic disease Diseases 0.000 description 3
- 229940035676 analgesics Drugs 0.000 description 3
- 239000000730 antalgic agent Substances 0.000 description 3
- 239000008346 aqueous phase Substances 0.000 description 3
- 230000003542 behavioural effect Effects 0.000 description 3
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 3
- 230000001413 cellular effect Effects 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000003086 colorant Substances 0.000 description 3
- 239000006071 cream Substances 0.000 description 3
- 230000009849 deactivation Effects 0.000 description 3
- 239000002270 dispersing agent Substances 0.000 description 3
- 239000003995 emulsifying agent Substances 0.000 description 3
- 239000000796 flavoring agent Substances 0.000 description 3
- 239000008273 gelatin Substances 0.000 description 3
- 229920000159 gelatin Polymers 0.000 description 3
- 235000019322 gelatine Nutrition 0.000 description 3
- 235000011852 gelatine desserts Nutrition 0.000 description 3
- 239000008103 glucose Substances 0.000 description 3
- 125000005843 halogen group Chemical group 0.000 description 3
- 125000005842 heteroatom Chemical group 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 3
- 230000009610 hypersensitivity Effects 0.000 description 3
- 125000002883 imidazolyl group Chemical group 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 230000006698 induction Effects 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 150000002611 lead compounds Chemical class 0.000 description 3
- 239000002609 medium Substances 0.000 description 3
- 230000028161 membrane depolarization Effects 0.000 description 3
- 230000035772 mutation Effects 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 229940005483 opioid analgesics Drugs 0.000 description 3
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 description 3
- 230000036278 prepulse Effects 0.000 description 3
- 239000003755 preservative agent Substances 0.000 description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 239000000829 suppository Substances 0.000 description 3
- 239000012730 sustained-release form Substances 0.000 description 3
- 238000004809 thin layer chromatography Methods 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- 238000001262 western blot Methods 0.000 description 3
- LXYUSXFFUYVKOV-UHFFFAOYSA-N 1,3-dioxole-4-carboxamide Chemical class NC(=O)C1=COCO1 LXYUSXFFUYVKOV-UHFFFAOYSA-N 0.000 description 2
- AXTGDCSMTYGJND-UHFFFAOYSA-N 1-dodecylazepan-2-one Chemical compound CCCCCCCCCCCCN1CCCCCC1=O AXTGDCSMTYGJND-UHFFFAOYSA-N 0.000 description 2
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 2
- WEEMDRWIKYCTQM-UHFFFAOYSA-N 2,6-dimethoxybenzenecarbothioamide Chemical compound COC1=CC=CC(OC)=C1C(N)=S WEEMDRWIKYCTQM-UHFFFAOYSA-N 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- XMIIGOLPHOKFCH-UHFFFAOYSA-N 3-phenylpropionic acid Chemical compound OC(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-N 0.000 description 2
- YUMYCPNZTXPUTQ-UHFFFAOYSA-N 4-(2-chloroethyl)piperidin-1-ium;chloride Chemical compound Cl.ClCCC1CCNCC1 YUMYCPNZTXPUTQ-UHFFFAOYSA-N 0.000 description 2
- KDSGFDGTUWELFP-UHFFFAOYSA-N 4-(4-methoxypiperidin-1-yl)aniline Chemical compound C1CC(OC)CCN1C1=CC=C(N)C=C1 KDSGFDGTUWELFP-UHFFFAOYSA-N 0.000 description 2
- NCKZXQFJRWRVJY-UHFFFAOYSA-N 4-[(4-cyanophenyl)methoxy]-3-methoxybenzoic acid Chemical compound COC1=CC(C(O)=O)=CC=C1OCC1=CC=C(C#N)C=C1 NCKZXQFJRWRVJY-UHFFFAOYSA-N 0.000 description 2
- 206010001497 Agitation Diseases 0.000 description 2
- 208000024827 Alzheimer disease Diseases 0.000 description 2
- 206010002091 Anaesthesia Diseases 0.000 description 2
- 241000416162 Astragalus gummifer Species 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- FOALRRUAVKVVHJ-UHFFFAOYSA-N C(#N)C1=CC=C(COC2=C(C=C(C(=O)Cl)C=C2)OC)C=C1 Chemical compound C(#N)C1=CC=C(COC2=C(C=C(C(=O)Cl)C=C2)OC)C=C1 FOALRRUAVKVVHJ-UHFFFAOYSA-N 0.000 description 2
- KMSHSVVCBPUPNH-UHFFFAOYSA-N COC=1C=C(C(=O)O)C=CC=1OCC1=CC=C(C=C1)OC(F)(F)F Chemical compound COC=1C=C(C(=O)O)C=CC=1OCC1=CC=C(C=C1)OC(F)(F)F KMSHSVVCBPUPNH-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 2
- 102100022188 Dihydropyrimidinase-related protein 1 Human genes 0.000 description 2
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- UGJMXCAKCUNAIE-UHFFFAOYSA-N Gabapentin Chemical compound OC(=O)CC1(CN)CCCCC1 UGJMXCAKCUNAIE-UHFFFAOYSA-N 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
- 239000007821 HATU Substances 0.000 description 2
- 101000900531 Homo sapiens Dihydropyrimidinase-related protein 1 Proteins 0.000 description 2
- 101000640020 Homo sapiens Sodium channel protein type 11 subunit alpha Proteins 0.000 description 2
- 208000035154 Hyperesthesia Diseases 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- 239000012097 Lipofectamine 2000 Substances 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- 208000012902 Nervous system disease Diseases 0.000 description 2
- 208000025966 Neurological disease Diseases 0.000 description 2
- 208000018737 Parkinson disease Diseases 0.000 description 2
- 229930182555 Penicillin Natural products 0.000 description 2
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- 229920002873 Polyethylenimine Polymers 0.000 description 2
- 208000003251 Pruritus Diseases 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- LCTONWCANYUPML-UHFFFAOYSA-N Pyruvic acid Chemical compound CC(=O)C(O)=O LCTONWCANYUPML-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 108020004459 Small interfering RNA Proteins 0.000 description 2
- 102100033974 Sodium channel protein type 11 subunit alpha Human genes 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- 229920001615 Tragacanth Polymers 0.000 description 2
- 108010053752 Voltage-Gated Sodium Channels Proteins 0.000 description 2
- 102000016913 Voltage-Gated Sodium Channels Human genes 0.000 description 2
- 208000027418 Wounds and injury Diseases 0.000 description 2
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 239000002671 adjuvant Substances 0.000 description 2
- 239000000443 aerosol Substances 0.000 description 2
- 230000037005 anaesthesia Effects 0.000 description 2
- 239000007900 aqueous suspension Substances 0.000 description 2
- 125000004104 aryloxy group Chemical group 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 230000009460 calcium influx Effects 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 229910002092 carbon dioxide Inorganic materials 0.000 description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 238000003501 co-culture Methods 0.000 description 2
- 229940110456 cocoa butter Drugs 0.000 description 2
- 235000019868 cocoa butter Nutrition 0.000 description 2
- 108010022822 collapsin response mediator protein-2 Proteins 0.000 description 2
- 238000005094 computer simulation Methods 0.000 description 2
- 125000004122 cyclic group Chemical group 0.000 description 2
- 230000001086 cytosolic effect Effects 0.000 description 2
- 230000006378 damage Effects 0.000 description 2
- 230000001419 dependent effect Effects 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000004520 electroporation Methods 0.000 description 2
- 201000011384 erythromelalgia Diseases 0.000 description 2
- 230000032050 esterification Effects 0.000 description 2
- 238000005886 esterification reaction Methods 0.000 description 2
- QEOZGTBBNDHZSK-UHFFFAOYSA-N ethyl 3-fluoro-4-hydroxybenzoate Chemical compound CCOC(=O)C1=CC=C(O)C(F)=C1 QEOZGTBBNDHZSK-UHFFFAOYSA-N 0.000 description 2
- MTZQAGJQAFMTAQ-UHFFFAOYSA-N ethyl benzoate Chemical compound CCOC(=O)C1=CC=CC=C1 MTZQAGJQAFMTAQ-UHFFFAOYSA-N 0.000 description 2
- 239000012091 fetal bovine serum Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 235000019634 flavors Nutrition 0.000 description 2
- 239000000499 gel Substances 0.000 description 2
- BRZYSWJRSDMWLG-CAXSIQPQSA-N geneticin Chemical compound O1C[C@@](O)(C)[C@H](NC)[C@@H](O)[C@H]1O[C@@H]1[C@@H](O)[C@H](O[C@@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](C(C)O)O2)N)[C@@H](N)C[C@H]1N BRZYSWJRSDMWLG-CAXSIQPQSA-N 0.000 description 2
- RWSXRVCMGQZWBV-WDSKDSINSA-N glutathione Chemical group OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-WDSKDSINSA-N 0.000 description 2
- 125000004438 haloalkoxy group Chemical group 0.000 description 2
- 229910052736 halogen Inorganic materials 0.000 description 2
- 150000002367 halogens Chemical class 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 238000001802 infusion Methods 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 208000014674 injury Diseases 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 230000003834 intracellular effect Effects 0.000 description 2
- 238000007913 intrathecal administration Methods 0.000 description 2
- 150000002500 ions Chemical class 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 239000000787 lecithin Substances 0.000 description 2
- 235000010445 lecithin Nutrition 0.000 description 2
- 229940067606 lecithin Drugs 0.000 description 2
- 239000006210 lotion Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 238000007726 management method Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 230000001404 mediated effect Effects 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 2
- DZNKOAWEHDKBEP-UHFFFAOYSA-N methyl 2-[6-[bis(2-methoxy-2-oxoethyl)amino]-5-[2-[2-[bis(2-methoxy-2-oxoethyl)amino]-5-methylphenoxy]ethoxy]-1-benzofuran-2-yl]-1,3-oxazole-5-carboxylate Chemical compound COC(=O)CN(CC(=O)OC)C1=CC=C(C)C=C1OCCOC(C(=C1)N(CC(=O)OC)CC(=O)OC)=CC2=C1OC(C=1OC(=CN=1)C(=O)OC)=C2 DZNKOAWEHDKBEP-UHFFFAOYSA-N 0.000 description 2
- 229920000609 methyl cellulose Polymers 0.000 description 2
- 239000001923 methylcellulose Substances 0.000 description 2
- 235000010981 methylcellulose Nutrition 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 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 description 2
- 125000002757 morpholinyl group Chemical group 0.000 description 2
- TXXHDPDFNKHHGW-UHFFFAOYSA-N muconic acid Chemical compound OC(=O)C=CC=CC(O)=O TXXHDPDFNKHHGW-UHFFFAOYSA-N 0.000 description 2
- 210000003928 nasal cavity Anatomy 0.000 description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 description 2
- 210000000929 nociceptor Anatomy 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 235000019198 oils Nutrition 0.000 description 2
- 239000002674 ointment Substances 0.000 description 2
- 208000019865 paroxysmal extreme pain disease Diseases 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 229940049954 penicillin Drugs 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 125000000843 phenylene group Chemical group C1(=C(C=CC=C1)*)* 0.000 description 2
- 229910052698 phosphorus Inorganic materials 0.000 description 2
- 239000006187 pill Substances 0.000 description 2
- 125000004193 piperazinyl group Chemical group 0.000 description 2
- 125000003386 piperidinyl group Chemical group 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 229920006316 polyvinylpyrrolidine Polymers 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 208000017692 primary erythermalgia Diseases 0.000 description 2
- 230000000069 prophylactic effect Effects 0.000 description 2
- 125000005550 pyrazinylene group Chemical group 0.000 description 2
- 125000005551 pyridylene group Chemical group 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 230000002829 reductive effect Effects 0.000 description 2
- 230000000717 retained effect Effects 0.000 description 2
- 238000002390 rotary evaporation Methods 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 210000003497 sciatic nerve Anatomy 0.000 description 2
- 210000001044 sensory neuron Anatomy 0.000 description 2
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 2
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 2
- 239000007921 spray Substances 0.000 description 2
- 229960002385 streptomycin sulfate Drugs 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- YMBCJWGVCUEGHA-UHFFFAOYSA-M tetraethylammonium chloride Chemical compound [Cl-].CC[N+](CC)(CC)CC YMBCJWGVCUEGHA-UHFFFAOYSA-M 0.000 description 2
- CFMYXEVWODSLAX-QOZOJKKESA-N tetrodotoxin Chemical compound O([C@@]([C@H]1O)(O)O[C@H]2[C@@]3(O)CO)[C@H]3[C@@H](O)[C@]11[C@H]2[C@@H](O)N=C(N)N1 CFMYXEVWODSLAX-QOZOJKKESA-N 0.000 description 2
- 229950010357 tetrodotoxin Drugs 0.000 description 2
- CFMYXEVWODSLAX-UHFFFAOYSA-N tetrodotoxin Natural products C12C(O)NC(=N)NC2(C2O)C(O)C3C(CO)(O)C1OC2(O)O3 CFMYXEVWODSLAX-UHFFFAOYSA-N 0.000 description 2
- 125000003396 thiol group Chemical group [H]S* 0.000 description 2
- 238000011200 topical administration Methods 0.000 description 2
- 235000010487 tragacanth Nutrition 0.000 description 2
- 239000000196 tragacanth Substances 0.000 description 2
- 229940116362 tragacanth Drugs 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
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 2
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 2
- 230000003313 weakening effect Effects 0.000 description 2
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-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
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 1
- WBYWAXJHAXSJNI-VOTSOKGWSA-M .beta-Phenylacrylic acid Natural products [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 description 1
- ZORQXIQZAOLNGE-UHFFFAOYSA-N 1,1-difluorocyclohexane Chemical compound FC1(F)CCCCC1 ZORQXIQZAOLNGE-UHFFFAOYSA-N 0.000 description 1
- DDMOUSALMHHKOS-UHFFFAOYSA-N 1,2-dichloro-1,1,2,2-tetrafluoroethane Chemical compound FC(F)(Cl)C(F)(F)Cl DDMOUSALMHHKOS-UHFFFAOYSA-N 0.000 description 1
- HUSYTLMIRXITQS-UHFFFAOYSA-N 1,3-benzodioxole-5-carboxamide Chemical compound NC(=O)C1=CC=C2OCOC2=C1 HUSYTLMIRXITQS-UHFFFAOYSA-N 0.000 description 1
- MYYYZNVAUZVXBO-UHFFFAOYSA-N 1-(bromomethyl)-3-(trifluoromethyl)benzene Chemical compound FC(F)(F)C1=CC=CC(CBr)=C1 MYYYZNVAUZVXBO-UHFFFAOYSA-N 0.000 description 1
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 1
- AMMPLVWPWSYRDR-UHFFFAOYSA-N 1-methylbicyclo[2.2.2]oct-2-ene-4-carboxylic acid Chemical compound C1CC2(C(O)=O)CCC1(C)C=C2 AMMPLVWPWSYRDR-UHFFFAOYSA-N 0.000 description 1
- BZYUMXXOAYSFOW-UHFFFAOYSA-N 2,3-dimethylthiophene Chemical class CC=1C=CSC=1C BZYUMXXOAYSFOW-UHFFFAOYSA-N 0.000 description 1
- HUHXLHLWASNVDB-UHFFFAOYSA-N 2-(oxan-2-yloxy)oxane Chemical class O1CCCCC1OC1OCCCC1 HUHXLHLWASNVDB-UHFFFAOYSA-N 0.000 description 1
- UPHOPMSGKZNELG-UHFFFAOYSA-N 2-hydroxynaphthalene-1-carboxylic acid Chemical compound C1=CC=C2C(C(=O)O)=C(O)C=CC2=C1 UPHOPMSGKZNELG-UHFFFAOYSA-N 0.000 description 1
- MLMQPDHYNJCQAO-UHFFFAOYSA-N 3,3-dimethylbutyric acid Chemical compound CC(C)(C)CC(O)=O MLMQPDHYNJCQAO-UHFFFAOYSA-N 0.000 description 1
- 125000005809 3,4,5-trimethoxyphenyl group Chemical group [H]C1=C(OC([H])([H])[H])C(OC([H])([H])[H])=C(OC([H])([H])[H])C([H])=C1* 0.000 description 1
- XLZYKTYMLBOINK-UHFFFAOYSA-N 3-(4-hydroxybenzoyl)benzoic acid Chemical compound OC(=O)C1=CC=CC(C(=O)C=2C=CC(O)=CC=2)=C1 XLZYKTYMLBOINK-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- ZRPLANDPDWYOMZ-UHFFFAOYSA-N 3-cyclopentylpropionic acid Chemical compound OC(=O)CCC1CCCC1 ZRPLANDPDWYOMZ-UHFFFAOYSA-N 0.000 description 1
- IUSDEKNMCOUBEE-UHFFFAOYSA-N 3-fluoro-4-hydroxybenzoic acid Chemical compound OC(=O)C1=CC=C(O)C(F)=C1 IUSDEKNMCOUBEE-UHFFFAOYSA-N 0.000 description 1
- ZSIFZEDSVXGFHP-UHFFFAOYSA-N 3-fluoro-4-hydroxybenzoyl chloride Chemical compound OC1=CC=C(C(Cl)=O)C=C1F ZSIFZEDSVXGFHP-UHFFFAOYSA-N 0.000 description 1
- 125000004207 3-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(OC([H])([H])[H])=C1[H] 0.000 description 1
- RJWBTWIBUIGANW-UHFFFAOYSA-N 4-chlorobenzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=C(Cl)C=C1 RJWBTWIBUIGANW-UHFFFAOYSA-N 0.000 description 1
- 125000004863 4-trifluoromethoxyphenyl group Chemical group [H]C1=C([H])C(OC(F)(F)F)=C([H])C([H])=C1* 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 206010002653 Anosmia Diseases 0.000 description 1
- 108090000145 Bacillolysin Proteins 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- HGAYUKTYIDUUMV-UHFFFAOYSA-N C(#N)C1=CC=C(COC2=C(C=C(C(=O)NC3=CC=C(C=C3)N3CCC(CC3)OC)C=C2)OC)C=C1 Chemical compound C(#N)C1=CC=C(COC2=C(C=C(C(=O)NC3=CC=C(C=C3)N3CCC(CC3)OC)C=C2)OC)C=C1 HGAYUKTYIDUUMV-UHFFFAOYSA-N 0.000 description 1
- XPHCBTZKROVBRH-UHFFFAOYSA-N C(#N)C1=CC=C(COC2=C(C=C(C(=O)OCC)C=C2)OC)C=C1 Chemical compound C(#N)C1=CC=C(COC2=C(C=C(C(=O)OCC)C=C2)OC)C=C1 XPHCBTZKROVBRH-UHFFFAOYSA-N 0.000 description 1
- DCERHCFNWRGHLK-UHFFFAOYSA-N C[Si](C)C Chemical compound C[Si](C)C DCERHCFNWRGHLK-UHFFFAOYSA-N 0.000 description 1
- 101100539164 Caenorhabditis elegans ubc-9 gene Proteins 0.000 description 1
- 206010058019 Cancer Pain Diseases 0.000 description 1
- WWZKQHOCKIZLMA-UHFFFAOYSA-N Caprylic acid Natural products CCCCCCCC(O)=O WWZKQHOCKIZLMA-UHFFFAOYSA-N 0.000 description 1
- WBYWAXJHAXSJNI-SREVYHEPSA-N Cinnamic acid Chemical compound OC(=O)\C=C/C1=CC=CC=C1 WBYWAXJHAXSJNI-SREVYHEPSA-N 0.000 description 1
- 206010010144 Completed suicide Diseases 0.000 description 1
- 206010010774 Constipation Diseases 0.000 description 1
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 description 1
- 206010012335 Dependence Diseases 0.000 description 1
- 239000004375 Dextrin Substances 0.000 description 1
- 229920001353 Dextrin Polymers 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
- 208000032131 Diabetic Neuropathies Diseases 0.000 description 1
- 239000004338 Dichlorodifluoromethane Substances 0.000 description 1
- 102100024425 Dihydropyrimidinase-related protein 3 Human genes 0.000 description 1
- 102100024443 Dihydropyrimidinase-related protein 4 Human genes 0.000 description 1
- 102100024441 Dihydropyrimidinase-related protein 5 Human genes 0.000 description 1
- 208000012661 Dyskinesia Diseases 0.000 description 1
- LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 0.000 description 1
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 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
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- 108010024636 Glutathione Proteins 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 101001053501 Homo sapiens Dihydropyrimidinase-related protein 3 Proteins 0.000 description 1
- 101001053490 Homo sapiens Dihydropyrimidinase-related protein 4 Proteins 0.000 description 1
- 101001053479 Homo sapiens Dihydropyrimidinase-related protein 5 Proteins 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- XQFRJNBWHJMXHO-RRKCRQDMSA-N IDUR Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(I)=C1 XQFRJNBWHJMXHO-RRKCRQDMSA-N 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 206010065390 Inflammatory pain Diseases 0.000 description 1
- 206010050296 Intervertebral disc protrusion Diseases 0.000 description 1
- PIWKPBJCKXDKJR-UHFFFAOYSA-N Isoflurane Chemical compound FC(F)OC(Cl)C(F)(F)F PIWKPBJCKXDKJR-UHFFFAOYSA-N 0.000 description 1
- YQEZLKZALYSWHR-UHFFFAOYSA-N Ketamine Chemical compound C=1C=CC=C(Cl)C=1C1(NC)CCCCC1=O YQEZLKZALYSWHR-UHFFFAOYSA-N 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- 229920000881 Modified starch Polymers 0.000 description 1
- TXXHDPDFNKHHGW-CCAGOZQPSA-N Muconic acid Natural products OC(=O)\C=C/C=C\C(O)=O TXXHDPDFNKHHGW-CCAGOZQPSA-N 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- HSHXDCVZWHOWCS-UHFFFAOYSA-N N'-hexadecylthiophene-2-carbohydrazide Chemical compound CCCCCCCCCCCCCCCCNNC(=O)c1cccs1 HSHXDCVZWHOWCS-UHFFFAOYSA-N 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
- 206010028813 Nausea Diseases 0.000 description 1
- 108010025020 Nerve Growth Factor Proteins 0.000 description 1
- 102000015336 Nerve Growth Factor Human genes 0.000 description 1
- 102000035092 Neutral proteases Human genes 0.000 description 1
- 108091005507 Neutral proteases Proteins 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 208000001294 Nociceptive Pain Diseases 0.000 description 1
- 102000007982 Phosphoproteins Human genes 0.000 description 1
- 108010089430 Phosphoproteins Proteins 0.000 description 1
- 206010036376 Postherpetic Neuralgia Diseases 0.000 description 1
- 208000037674 Primary erythromelalgia Diseases 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- 208000004756 Respiratory Insufficiency Diseases 0.000 description 1
- 206010038678 Respiratory depression Diseases 0.000 description 1
- 102100029807 SUMO-conjugating enzyme UBC9 Human genes 0.000 description 1
- 101710201957 SUMO-conjugating enzyme UBC9 Proteins 0.000 description 1
- 206010039897 Sedation Diseases 0.000 description 1
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 1
- 208000010261 Small Fiber Neuropathy Diseases 0.000 description 1
- 206010073928 Small fibre neuropathy Diseases 0.000 description 1
- 108010052164 Sodium Channels Proteins 0.000 description 1
- 102000018674 Sodium Channels Human genes 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 208000006011 Stroke Diseases 0.000 description 1
- 238000000692 Student's t-test Methods 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 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
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000036982 action potential Effects 0.000 description 1
- 239000012190 activator Substances 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 239000000853 adhesive Substances 0.000 description 1
- 230000001070 adhesive effect Effects 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 229910001413 alkali metal ion Inorganic materials 0.000 description 1
- 229910001420 alkaline earth metal ion Inorganic materials 0.000 description 1
- 125000003282 alkyl amino group Chemical group 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 230000036592 analgesia Effects 0.000 description 1
- 239000012491 analyte Substances 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 239000008135 aqueous vehicle Substances 0.000 description 1
- 150000001491 aromatic compounds Chemical class 0.000 description 1
- 206010003246 arthritis Diseases 0.000 description 1
- 235000021311 artificial sweeteners Nutrition 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 125000004622 benzoxazinyl group Chemical group O1NC(=CC2=C1C=CC=C2)* 0.000 description 1
- GONOPSZTUGRENK-UHFFFAOYSA-N benzyl(trichloro)silane Chemical compound Cl[Si](Cl)(Cl)CC1=CC=CC=C1 GONOPSZTUGRENK-UHFFFAOYSA-N 0.000 description 1
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 1
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 1
- 125000002619 bicyclic group Chemical group 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 229920002988 biodegradable polymer Polymers 0.000 description 1
- 239000004621 biodegradable polymer Substances 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 239000005388 borosilicate glass Substances 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 150000004657 carbamic acid derivatives Chemical class 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 238000001460 carbon-13 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 150000003943 catecholamines Chemical class 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 230000030833 cell death Effects 0.000 description 1
- 230000033077 cellular process Effects 0.000 description 1
- 239000013522 chelant Substances 0.000 description 1
- YRQNKMKHABXEJZ-UVQQGXFZSA-N chembl176323 Chemical compound C1C[C@]2(C)[C@@]3(C)CC(N=C4C[C@]5(C)CCC6[C@]7(C)CC[C@@H]([C@]7(CC[C@]6(C)[C@@]5(C)CC4=N4)C)CCCCCCCC)=C4C[C@]3(C)CCC2[C@]2(C)CC[C@H](CCCCCCCC)[C@]21C YRQNKMKHABXEJZ-UVQQGXFZSA-N 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- KYKAJFCTULSVSH-UHFFFAOYSA-N chloro(fluoro)methane Chemical compound F[C]Cl KYKAJFCTULSVSH-UHFFFAOYSA-N 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 235000013985 cinnamic acid Nutrition 0.000 description 1
- 229930016911 cinnamic acid Natural products 0.000 description 1
- 210000003703 cisterna magna Anatomy 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 230000006395 clathrin-mediated endocytosis Effects 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000007906 compression Methods 0.000 description 1
- 230000003750 conditioning effect Effects 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 125000000000 cycloalkoxy group Chemical group 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- 125000000131 cyclopropyloxy group Chemical group C1(CC1)O* 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000002939 deleterious effect Effects 0.000 description 1
- 235000019425 dextrin Nutrition 0.000 description 1
- PXBRQCKWGAHEHS-UHFFFAOYSA-N dichlorodifluoromethane Chemical compound FC(F)(Cl)Cl PXBRQCKWGAHEHS-UHFFFAOYSA-N 0.000 description 1
- 235000019404 dichlorodifluoromethane Nutrition 0.000 description 1
- 229940042935 dichlorodifluoromethane Drugs 0.000 description 1
- 229940087091 dichlorotetrafluoroethane Drugs 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 1
- 125000000597 dioxinyl group Chemical group 0.000 description 1
- 238000002224 dissection Methods 0.000 description 1
- 230000009429 distress Effects 0.000 description 1
- MOTZDAYCYVMXPC-UHFFFAOYSA-N dodecyl hydrogen sulfate Chemical compound CCCCCCCCCCCCOS(O)(=O)=O MOTZDAYCYVMXPC-UHFFFAOYSA-N 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 230000007831 electrophysiology Effects 0.000 description 1
- 238000002001 electrophysiology Methods 0.000 description 1
- 230000001804 emulsifying effect Effects 0.000 description 1
- 239000002702 enteric coating Substances 0.000 description 1
- 238000009505 enteric coating Methods 0.000 description 1
- 210000002615 epidermis Anatomy 0.000 description 1
- 230000001667 episodic effect Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- AFAXGSQYZLGZPG-UHFFFAOYSA-N ethanedisulfonic acid Chemical compound OS(=O)(=O)CCS(O)(=O)=O AFAXGSQYZLGZPG-UHFFFAOYSA-N 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- 125000001033 ether group Chemical group 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 description 1
- 229940093471 ethyl oleate Drugs 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 239000000835 fiber Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000003818 flash chromatography Methods 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 150000004675 formic acid derivatives Chemical class 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 229960002870 gabapentin Drugs 0.000 description 1
- 210000000609 ganglia Anatomy 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000003349 gelling agent Substances 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 239000000174 gluconic acid Substances 0.000 description 1
- 235000012208 gluconic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 229960003180 glutathione Drugs 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 210000003128 head Anatomy 0.000 description 1
- 238000012203 high throughput assay Methods 0.000 description 1
- 210000000548 hind-foot Anatomy 0.000 description 1
- 239000008240 homogeneous mixture Substances 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- 230000037417 hyperactivation Effects 0.000 description 1
- 230000002102 hyperpolarization Effects 0.000 description 1
- 238000003018 immunoassay Methods 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- 238000000126 in silico method Methods 0.000 description 1
- 238000000099 in vitro assay Methods 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 230000004941 influx Effects 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 238000001361 intraarterial administration Methods 0.000 description 1
- 230000006525 intracellular process Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 229960002725 isoflurane Drugs 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 230000007803 itching Effects 0.000 description 1
- 229960003299 ketamine Drugs 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 238000011813 knockout mouse model Methods 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 230000004777 loss-of-function mutation Effects 0.000 description 1
- 210000003141 lower extremity Anatomy 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 210000004705 lumbosacral region Anatomy 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 1
- 239000001095 magnesium carbonate Substances 0.000 description 1
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 238000012423 maintenance Methods 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
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 229910021645 metal ion Inorganic materials 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- WBYWAXJHAXSJNI-UHFFFAOYSA-N methyl p-hydroxycinnamate Natural products OC(=O)C=CC1=CC=CC=C1 WBYWAXJHAXSJNI-UHFFFAOYSA-N 0.000 description 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 235000019426 modified starch Nutrition 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- 229960005181 morphine Drugs 0.000 description 1
- 239000002324 mouth wash Substances 0.000 description 1
- 201000006417 multiple sclerosis Diseases 0.000 description 1
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-N n-hexanoic acid Natural products CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- KVBGVZZKJNLNJU-UHFFFAOYSA-N naphthalene-2-sulfonic acid Chemical compound C1=CC=CC2=CC(S(=O)(=O)O)=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 230000003533 narcotic effect Effects 0.000 description 1
- 235000021096 natural sweeteners Nutrition 0.000 description 1
- 230000008693 nausea Effects 0.000 description 1
- 239000006199 nebulizer Substances 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 229940053128 nerve growth factor Drugs 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 238000010606 normalization Methods 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 238000001543 one-way ANOVA Methods 0.000 description 1
- 239000000014 opioid analgesic Substances 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 239000006186 oral dosage form Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 150000002895 organic esters Chemical class 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000006072 paste Substances 0.000 description 1
- 235000010603 pastilles Nutrition 0.000 description 1
- 239000001814 pectin Substances 0.000 description 1
- 235000010987 pectin Nutrition 0.000 description 1
- 229920001277 pectin Polymers 0.000 description 1
- 239000003961 penetration enhancing agent Substances 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 210000001428 peripheral nervous system Anatomy 0.000 description 1
- 208000033808 peripheral neuropathy Diseases 0.000 description 1
- 210000004345 peroneal nerve Anatomy 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- RGCLLPNLLBQHPF-HJWRWDBZSA-N phosphamidon Chemical compound CCN(CC)C(=O)C(\Cl)=C(/C)OP(=O)(OC)OC RGCLLPNLLBQHPF-HJWRWDBZSA-N 0.000 description 1
- 239000003504 photosensitizing agent Substances 0.000 description 1
- IEQIEDJGQAUEQZ-UHFFFAOYSA-N phthalocyanine Chemical compound N1C(N=C2C3=CC=CC=C3C(N=C3C4=CC=CC=C4C(=N4)N3)=N2)=C(C=CC=C2)C2=C1N=C1C2=CC=CC=C2C4=N1 IEQIEDJGQAUEQZ-UHFFFAOYSA-N 0.000 description 1
- 125000004194 piperazin-1-yl group Chemical group [H]N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 description 1
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 1
- 229920000747 poly(lactic acid) Polymers 0.000 description 1
- 239000004626 polylactic acid Substances 0.000 description 1
- 230000004481 post-translational protein modification Effects 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000012746 preparative thin layer chromatography Methods 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 239000003380 propellant Substances 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 230000006916 protein interaction Effects 0.000 description 1
- 230000009145 protein modification Effects 0.000 description 1
- YQUVCSBJEUQKSH-UHFFFAOYSA-N protochatechuic acid Natural products OC(=O)C1=CC=C(O)C(O)=C1 YQUVCSBJEUQKSH-UHFFFAOYSA-N 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 230000005180 public health Effects 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- JUJWROOIHBZHMG-UHFFFAOYSA-O pyridinium Chemical compound C1=CC=[NH+]C=C1 JUJWROOIHBZHMG-UHFFFAOYSA-O 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 229940107700 pyruvic acid Drugs 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 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
- 230000009257 reactivity Effects 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 238000004007 reversed phase HPLC Methods 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 238000007423 screening assay Methods 0.000 description 1
- 230000036280 sedation Effects 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- 229920002379 silicone rubber Polymers 0.000 description 1
- 239000004945 silicone rubber Substances 0.000 description 1
- 238000009097 single-agent therapy Methods 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M sodium bicarbonate Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- 239000001593 sorbitan monooleate Substances 0.000 description 1
- 235000011069 sorbitan monooleate Nutrition 0.000 description 1
- 229940035049 sorbitan monooleate Drugs 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 210000000278 spinal cord Anatomy 0.000 description 1
- 238000012453 sprague-dawley rat model Methods 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 125000003107 substituted aryl group Chemical group 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 210000000331 sympathetic ganglia Anatomy 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 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
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 230000008719 thickening Effects 0.000 description 1
- 210000001519 tissue Anatomy 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
- 230000000699 topical effect Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 230000037317 transdermal delivery Effects 0.000 description 1
- 238000010361 transduction Methods 0.000 description 1
- 230000026683 transduction Effects 0.000 description 1
- 239000012096 transfection reagent Substances 0.000 description 1
- 230000032258 transport Effects 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- CYRMSUTZVYGINF-UHFFFAOYSA-N trichlorofluoromethane Chemical compound FC(Cl)(Cl)Cl CYRMSUTZVYGINF-UHFFFAOYSA-N 0.000 description 1
- 229940029284 trichlorofluoromethane Drugs 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- 210000000427 trigeminal ganglion Anatomy 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- WKOLLVMJNQIZCI-UHFFFAOYSA-N vanillic acid Chemical compound COC1=CC(C(O)=O)=CC=C1O WKOLLVMJNQIZCI-UHFFFAOYSA-N 0.000 description 1
- TUUBOHWZSQXCSW-UHFFFAOYSA-N vanillic acid Natural products COC1=CC(O)=CC(C(O)=O)=C1 TUUBOHWZSQXCSW-UHFFFAOYSA-N 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 239000011345 viscous material Substances 0.000 description 1
- 102000038650 voltage-gated calcium channel activity Human genes 0.000 description 1
- 108091023044 voltage-gated calcium channel activity Proteins 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 229960001600 xylazine Drugs 0.000 description 1
- BPICBUSOMSTKRF-UHFFFAOYSA-N xylazine Chemical compound CC1=CC=CC(C)=C1NC1=NCCCS1 BPICBUSOMSTKRF-UHFFFAOYSA-N 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/452—Piperidinium derivatives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4525—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with oxygen as a ring hetero atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
- C07D295/135—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
- C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
- C07D295/182—Radicals derived from carboxylic acids
- C07D295/185—Radicals derived from carboxylic acids from aliphatic carboxylic acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
- C07D317/62—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to atoms of the carbocyclic ring
- C07D317/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
本发明提供了能调节Nav 1.7蛋白的量的化合物以及使用这种化合物的方法,Nav 1.7蛋白是存在于细胞表面的疼痛信号传导中的关键蛋白质。特别地,本发明的化合物通过调节CRMP2的SUMO化来调节细胞表面上Nav 1.7蛋白的量。因此,本发明的化合物能够用于治疗与细胞表面上Nav 1.7蛋白的存在和/或激活相关和/或与CRMP2的SUMO化相关的各种临床状况。
Description
相关申请的交叉引用
本申请要求于2015年10月7日提交的美国临时专利申请No.62/238,182的优先权,其全部内容通过引用并入本文。
技术领域
本发明涉及能够调节存在于神经元表面上的电压门控钠通道Nav1.7蛋白的量的化合物以及使用这种化合物的方法。具体而言,据信本发明的化合物通过抑制CRMP2的SUMO化来调节细胞表面上Nav1.7蛋白的量,其中SUMO化是添加小泛素样修饰体(SUMO)。
背景技术
慢性疼痛,且具体而言神经性疼痛,影响数百万人,花费数十亿美元,并且是发病、痛苦和自杀的主要原因。尽管一些慢性疼痛状况可以通过现有药物得到足够治疗,但大量患者即使复方用药也无法实现足够的疼痛缓解。此外,目前可用的阿片类镇痛疗法(通常仅部分有效)常常伴有许多副作用,这些副作用限制了它们的临床疗效,包括耐受性和成瘾性。
目前在分子水平和细胞水平上对神经性疼痛机制的理解是不完整的。由于这样,常规处方镇痛药物仅在大约三分之一受折磨的患者中取得成功。
因此,需要新的研究和治疗方法来进一步了解疼痛机制,从而为特定的且更有效的治疗开辟新的途径。
发明内容
本发明的一些方面涉及CRMP2的SUMO化抑制剂。据信抑制CRMP2的SUMO化引起细胞表面上Nav1.7蛋白的数量的减少,从而缓解与细胞表面Nav1.7的过多存在和/或超激活相关的各种临床状况。在一些实施方式中,CRMP2的SUMO化抑制剂是具有下式的化合物:
Ara1–La1–Ara2–Ra1 (化合物I)
其中Ara1是任选取代的苯基;La1是具有氢键受体部分的连接基团;Ara2是亚苯基、亚吡啶基或亚吡嗪基,其各自被任选取代;Ra1是具有至少一个氢键受体的杂环基或杂烷基;Arb1是苯并[d][1,3]二氧杂环戊烯基、苯并[d]噁唑基、苯并[d]异噁唑基、苯并[d]咪唑基、萘基或喹啉基;Lb1是构象上受限的连接基团(conformationally constrained linker);Rb1是杂环基或氮杂烷基;Arc1是2,3-二氢苯并[b][1,4]二噁英基、喹啉酮基、苯并噁嗪基、喹唑啉基或喹喔啉基;Lc1是具有氢键受体部分的连接基团;并且Rc1是具有至少一个氢键受体的杂环基或杂烷基。一种式I的具体化合物具有下式:
其中,Ara1和Ra1是本文限定的那些。
附图说明
图1是条形图,示出了本发明的代表性化合物对培养的大鼠背根神经节(DRG)神经元中藜芦碱(veratradine)诱导胞质Na+增加的减弱能力。
图2至图4以图示形式示出了表现本发明的化合物抑制大鼠DRG中河豚毒素敏感(TTX-S)的NaV1.7电流的实验结果。在这些图的每幅图中,子图A是激活的图解汇总,子图B是失活拟合的图解汇总,子图C是电流-电压关系的图,以及子图D示出了用DMSO或本发明的化合物处理的大鼠DRG的使用依赖性失活。
图5是本发明的化合物抑制大鼠和人DRG中TTX-S NaV1.7电流的实验结果。子图A示出了代表性钠电流迹线族。子图B示出了化合物AZ002的总结峰值电流。子图C示出了用DMSO或本发明的化合物处理的大鼠DRG的激活和失活拟合。子图D是示出了混合的神经胶质-DRG共培养两种人DRG(黄色箭头)的照片,证明与AZ002过夜孵育不影响细胞形态或健康。子图E示出了电流迹线族,证明了用AZ002处理的人DRG中H-无限减去的(即,NaV1.7)电流的抑制。
具体实施方式
定义:除非上下文另有要求,否则在整个说明书中使用以下定义。“烷基”是指一至十二个,典型地一至六个碳原子的饱和直链单价烃部分或三至十二个,优选三至六个碳原子的饱和支链单价烃部分。示例性的烷基基团包括但不限于,甲基、乙基、正丙基、2-丙基、叔丁基、戊基等。“亚烷基”是指一至十二个,典型地一至六个碳原子的饱和直链二价烃部分或三至十二个,优选三至六个碳原子的支链饱和二价烃部分。示例性的亚烷基基团包括但不限于,亚甲基、亚乙基、亚丙基、亚丁基、亚戊基等。“芳基”是指6至15个环原子的单价单环、双环或三环芳烃部分,其在环结构内任选地被一个或多个,优选一个、两个或三个取代基取代。当芳基基团中存在两个或更多个取代基时,各取代基是独立选择的。术语“卤代”、“卤素”和“卤化物”在本文中可互换使用并且指氟、氯、溴或碘。“卤代烷基”是指如本文所限定的烷基基团,其中一个或多个氢原子被相同或不同的卤素原子替代。术语“卤代烷基”还包括其中全部烷基氢原子被卤素原子替代的全卤代烷基基团。示例性的卤代烷基基团包括但不限于,–CH2Cl、–CF3、–CH2CF3、–CH2CCl3等。“杂环基”意指三至八个环原子的非芳香族单环部分,其中一个或两个环原子是选自N、O或S(O)n(其中n是0至2的整数)的杂原子,其余的环原子是C,其中一个或两个C原子可任选为羰基基团。杂环基环可任选独立地被一个或多个,优选一个、两个或三个取代基取代。当杂环基基团中存在两个或更多个取代基时,各取代基是独立选择的。“药学上可接受的赋形剂”是指用于制备通常安全、无毒并且在生物学上或其它方面均合乎需要的药物组合物的赋形剂,并且包括兽医用途以及人类药学用途可接受的赋形剂。化合物的“药学上可接受的盐”是指药学上可接受的且具有所需的母体化合物药理学活性的盐。这样的盐包括:(1)酸加成盐,与无机酸形成的,诸如盐酸、氢溴酸、硫酸、硝酸、磷酸等;或与有机酸形成的,诸如乙酸、丙酸、己酸、环戊烷丙酸、乙醇酸、丙酮酸、乳酸、丙二酸、琥珀酸、苹果酸,马来酸,富马酸、酒石酸、柠檬酸、苯甲酸、3-(4-羟基苯甲酰基)苯甲酸、肉桂酸、扁桃酸、甲磺酸、乙磺酸、1,2-乙烷-二磺酸、2-羟基乙磺酸、苯磺酸、4-氯苯磺酸、2-萘磺酸、4-甲苯磺酸、樟脑磺酸、4-甲基双环[2.2.2]-辛-2-烯-1-羧酸、葡萄糖庚酸、3-苯丙酸、三甲基乙酸、叔丁基乙酸、月桂基硫酸、葡萄糖酸、谷氨酸、羟基萘酸、水杨酸、硬脂酸,粘康酸等;或(2)当母体化合物中存在的酸性质子被金属离子替代时形成的盐,例如碱金属离子、碱土金属离子或铝离子;或与有机碱配位,诸如乙醇胺、二乙醇胺、三乙醇胺、氨丁三醇、N-甲基葡糖胺等。术语“前体药(pro-drug)”和“前药(prodrug)”在本文中可互换使用,并且是指当将这种前药给药于哺乳动物受试者时,体内释放根据式I的活性母体药物的任何化合物。式I的化合物的前药通过修饰式I的化合物中存在的一个或多个官能团来制备,通过这种方式,修饰可以在体内断裂以释放母体化合物。前药包括式I的化合物,其中式I的化合物中的羟基、氨基或巯基与任何可在体内断裂以分别再生游离的羟基、氨基或巯基的基团键合。前药的实例包括但不限于,式I的化合物中的羟基官能团的酯(例如乙酸酯、甲酸酯和苯甲酸酯衍生物)和氨基甲酸酯(例如N,N-二甲基氨基羰基)等。“保护基团”是指除烷基基团之外的部分,当其连接至分子中的反应基时掩蔽、减少或阻止其反应性。保护基团的实例见于T.W.Greene和P.G.M.Wuts的Protective Groups in Organic Synthesis,第3版,John Wiley&Sons,New York,1999和Harrison和Harrison等人的Compendium ofSynthetic Organic Methods,Vols.1-8(John Wiley and Sons,1971-1996)中,其全部内容通过引用并入本文。代表性的羟基保护基包括酰基基团、苄基和三苯甲基醚、四氢吡喃基醚、三烷基甲硅烷基醚和烯丙基醚。代表性的氨基保护基包括甲酰基、乙酰基、三氟乙酰基、苄基、苄氧羰基(CBZ)、叔丁氧羰基(Boc)、三甲基甲硅烷基(TMS)、2-三甲基甲硅烷基-乙磺酰基(SES)、三苯甲基和取代的三苯甲基基团、烯丙氧基羰基、9-芴甲氧基羰基(FMOC)、硝基-藜芦氧基羰基(NVOC)等。“对应的保护基团”意指与其所连接的杂原子(即,N、O、P或S)对应的适当保护基团。“治疗有效量”意指当向哺乳动物给药以治疗疾病时,足以达到该疾病的这种治疗效果的化合物的量。“治疗有效量”将根据化合物、疾病及其严重程度和待治疗的哺乳动物的年龄、体重等而变化。对疾病的“治疗(treating)”或“治疗(treatment)”包括:(1)预防疾病,即导致疾病的临床症状在可能暴露于或倾向于该疾病但尚未经历或表现该疾病症状的哺乳动物中不能发展;(2)抑制疾病,即阻止或减少疾病或其临床症状的发展;或(3)缓解疾病,即导致疾病或其临床症状的消退。当描述化学反应时,术语“处理”、“接触”和“反应”在本文中可互换使用,并且是指在适当条件下添加或混合两种或更多种试剂以产生指定的和/或期望的产物。应该理解的是,产生指定的和/或期望的产物的反应不一定直接由最初添加的两种试剂的组合发生,即在混合物中可能产生一种或多种中间体,其最终引起指定的和/或期望的产物的形成。如本文所用,当涉及变量时术语“上文限定的那些”和“本文限定的那些”通过引用并入变量的广义定义,若有的话,也并入任何狭义的和/或优选的、更优选的以及最优选的定义。
本发明的化合物:慢性疼痛是主要的公共健康问题,影响超过1亿美国人。阿片类药物是强力镇痛药,以及是许多类型疼痛的疼痛管理的基础。然而,阿片类药物会产生许多副作用,包括便秘、恶心、精神恍惚和呼吸抑制,有时会导致死亡。靶向电压门控钠通道Nav1.7(与广泛范围的疼痛状况相关的蛋白质)已经成为开发疼痛疗法的一种策略。
本发明的一些方面基于本发明人发现的化合物,其可以直接或间接调节存在于细胞表面上Nav1.7蛋白的量。因此,本发明的化合物可以用于治疗与细胞表面上存在的Nav1.7相关的任何数量的临床状况。在本发明的一种具体实施方式中,本发明的化合物用于治疗包括慢性和/或急性疼痛的疼痛。
据信电压门控的Nav1.7钠通道优先在与伤害性疼痛相关的神经节内(包括背根神经节(DRG)、三叉神经节和交感神经节)的外周神经系统中表达。在负责疼痛信号转导的伤害性神经元中,该通道调节激发动作电位响应刺激所需的电压激活阈值。功能增强型突变,即降低用于启动动作电位的Nav1.7电流阈值的那些突变,会产生触摸痛,一种较低的疼痛刺激阈值。这种突变是疼痛综合征的原因,包括红斑性肢痛、阵发性剧痛症和小纤维神经病变。
存在于细胞表面的Nav1.7的增加也与糖尿病神经病变、炎症、随后的坐骨神经联合压迫、髓核应用模型的腰椎间盘突出和保留性神经损伤(SNI)后导致的疼痛相关。相反,Nav1.7中的功能丧失型突变阻止刺激达到传播疼痛的阈值。具有这种突变的患者表现为痛觉完全丧失。此外,DRG感觉神经元中疱疹载体介导的Nav1.7的敲减明显阻止了响应于弗氏完全佐剂的痛觉过敏的发展(即,对疼痛刺激的响应增加)。因此,Nav1.7对于疼痛转导既是充分的,也是必需的。事实上,正如这种作用的证据,已经表明,Nav1.7敲除小鼠在炎性和神经性疼痛模型中不能发展痛觉过敏,但也不表达表型缺陷。
不受任何理论束缚,据信本发明的化合物调节存在于细胞表面上的Nav1.7蛋白的量,并因此调节由该蛋白质控制的细胞兴奋性。特别地,据信本发明的化合物调节(例如抑制)细胞内过程,该细胞内过程负责实现特定电压门控钠通道向细胞表面的细胞运输,从而选择性地减少在细胞表面上该通道的存在(即,Nav1.7蛋白)。
不受任何理论的限制,据信本发明的化合物被认为抑制CRMP2的SUMO化过程。SUMO化是参与各种细胞过程的翻译后修饰。术语“SUMO”是指小泛素样修饰体(SmallUbiquitin-like Modifier)。SUMO蛋白是与细胞中的靶蛋白共价连接和分离以修饰其功能的小蛋白质家族。如本文所用,调节或抑制“SUMO化(SUMOylation)”或调节或抑制“SUMO化过程(SUMOylation process)”意指调节或抑制SUMO蛋白的连接和/或在连接SUMO蛋白后调节或抑制蛋白的修饰。
存在于细胞表面上的Nav1.7蛋白的量部分通过CRMP2蛋白(即CRMP2)的SUMO化来调节。CRMP2是脑衰反应调节蛋白(CRMP)家族的成员,其由5种具有相似分子大小(60-66kDa)的细胞内磷蛋白(CRMP1、CRMP2、CRMP3、CRMP4、CRMP5)组成。已经发现,可以调节CRMP2的表达或生物学活性的化合物也可以用于治疗与神经疾病相关的临床状况,诸如多发性硬化症、阿尔茨海默氏病、帕金森氏病和中风。因此,在一些实施方式中,本发明的化合物可以用于治疗神经疾病,诸如阿尔茨海默氏病、帕金森氏病和/或中风,包括与这些疾病中的一些相关的疼痛。
关于疼痛治疗,本发明的化合物可以用于治疗各种类型的疼痛,包括慢性疼痛和急性疼痛、和瘙痒以及嗅觉丧失。可以用本发明化合物治疗的示例性慢性疼痛包括但不限于,癌性疼痛、烧伤疼痛、关节炎疼痛、化学疗法诱导的外周神经病变、疱疹后神经痛、发作性疼痛诸如原发性红斑性肢痛症和阵发性剧痛症等。可由本发明的化合物治疗的示例性急性疼痛包括但不限于,毒热痛、瘙痒和手术疼痛。
与使用阿片类化合物的传统疼痛治疗相比,本发明化合物的一些优点包括但不限于,无运动障碍或镇静作用、更高效并且在给定的剂量水平下与吗啡和加巴喷丁有相当的效力,以及与麻醉镇痛药相比,不存在或极大地减少了奖赏效应的可能性和滥用的可能性。
本发明的其它方面包括用于治疗受试者疼痛的方法,所述方法包括向需要这种治疗的受试者给药治疗有效量的本发明化合物。本发明的另一个方面包括用于治疗与细胞表面上Nav1.7蛋白的存在和/或激活相关的临床状况的方法,所述方法包括向患有与细胞表面上Nav1.7蛋白的存在和/或激活有关的临床状况的受试者给药治疗有效量的本发明的化合物从而减少细胞表面上Nav1.7蛋白的量。不受任何理论的限制,据信本发明的化合物通过抑制CRMP2的SUMO化来减少神经元细胞表面上存在的Nav1.7的量。
本发明的一些代表性化合物包括但不限于,具有下式的化合物:
Ara1–La1–Ara2–Ra1 (化合物I)
在式I的化合物中,Ara1是任选取代的芳基,诸如苯基或吡啶。在一种实施方式中,Ara1是在3-、4-和/或5-位上具有取代基的取代苯基(相对于具有La1的碳,该碳任意指定为C1-位)。式I的化合物中的苯基基团(例如,Ara1和Ara2)(或本发明化合物中任何其它苯基基团)的示例性取代基包括烷氧基(例如甲氧基、异丙氧基等)、环烷氧基(例如环丙氧基)、芳氧基、(例如苯氧基,其中苯氧基的苯基基团任选如本文所述的被取代)、烷基、卤代烷基、卤代烷氧基(即,R-O-,其中R为卤代烷基,诸如三氟甲氧基等)、氟、氰基、芳烷氧基(即,Ar-R-O-,其中Ar是芳基并且R是亚烷基,诸如苄氧基,其中芳基基团任选被1-3个取代基取代,诸如上文所述的那些)和杂环基烷氧基(即,Het-R-O-,其中Het是杂环基并且R是亚烷基)。通常地,苯基Ara1的3-和/或4-位被相对疏水的醚基团取代。苯基Ara1的5-位通常被H-键受体取代。术语“H-键受体”和“H-键受体部分”在本文中可互换使用,并且指具有孤对电子的杂原子(例如,O、N、S、P等),该孤对电子可以与具有结合至高度电负性原子(诸如氮(N)、氧(O)或硫(S)等)的氢原子的分子形成氢键。参见例如en.wikipedia.org/wiki/Hydrogen_bond。适合Ara1的示例性H-键受体包括但不限于,含氧取代基诸如烷氧基和卤代烷氧基(例如,甲氧基、乙氧基、丙氧基、异丙氧基和三氟甲氧基)。
式I的化合物的La1是具有氢键受体部分的连接基团。在一种具体的实施方式中,La1是下式的部分:-C(=O)-NR-,其中R是氢、烷基或氮保护基团。在另一种实施方式中,La1是咪唑基部分(例如,在环的1,3-位上具有两个咪唑基的N-原子)。
式I的化合物的Ara2是亚苯基、亚吡啶基或亚吡嗪基,其各自被1-3个取代基任选取代,每个取代基独立地被选择。合适的取代基包括上述那些。应该理解的是,所有的Ara2都被Ra1取代,因此当提及Ara2被取代时,意指Ara2具有除了Ra1之外的至少一种其它取代基。通常Ra1在相对于La1基团的对位被取代。特别地,Ara2的适合的取代基包括卤素(例如氯、溴、碘和/或氟)、烷基、烷氧基、卤代烷基、烷基氨基、烷氧基烷基氨基等。
式I的化合物的Ra1是具有至少一个氢键受体的杂环基或杂烷基。适合Ra1的示例性杂环基包括但不限于,哌嗪-1-基(例如4-甲基或4-烷基哌嗪-1-基)、吗啉基、吡咯烷基、哌啶基等。可替代地,Ra1可以是下式的部分:-NH-(CH2)m-OR3,或下式的部分:-NH-(CH2)m-N(R4)(R5),其中m=整数2或3,R3是氢、烷基或羟基保护基团,并且R4和R5独立地选自由氢、烷基、环烷基组成的组,或R4和R5与它们所连接的氮原子一起形成取代的或未取代的环体系,任选地在环体系内具有一个或多个额外的杂原子。
在其它实施方式中,Ra1是杂烷基。通常地,Ra1的杂烷基包括H-键受体,诸如碱性胺基基团、羰基(即,-C(=O)-)基团、烷氧基、芳氧基或其组合。
在一种实施方式中,化合物I具有下式:
其中Ara1和Ra1是本文限定的那些。Ara1的具体实例包括但不限于,3,5-二甲氧基苯基;3-甲氧基苯基;3-异丙氧基苯基;3,4,5-三甲氧基苯基;3-氟-4-[2-(哌啶-1-基)乙氧基]苯基或其盐;3-甲氧基-4-[(4-三氟甲氧基苯基)甲氧基]苯基;苯并[d][1,3]二氧杂环戊烯-5-基;3-氟-4-[2-(吗啉基)乙氧基]苯基;3-甲氧基-4-[(3-氟苯基)甲氧基]苯基;3-甲氧基-4-[(4-氟苯基)甲氧基]苯基;3-甲氧基-4-[(3-三氟甲基苯基)甲氧基]苯基;3-甲氧基-4-[(4-氰基苯基)甲氧基]苯基;及类似物。Ra1的具体实例包括但不限于,4-甲基哌嗪基及其盐;4-乙酰基哌嗪基;4-甲氧基哌嗪基;以及其它取代的哌嗪基和哌啶基部分。
一般而言,可以调节(例如干扰或抑制)CRMP2的SUMO化的任何化合物都在本发明的范围内。这样的化合物可以通过使用实施例部分中公开的计算机(in silico)或体外测定方法轻易鉴别。为开发可用于控制神经元细胞表面上Nav1.7的数目(即量)的CRMP2的SUMO化抑制剂,使用高通量测定来测试E2 SUMO缀合酶Ubc9与CRMP2结合的能力。简言之,结合至Ni-螯合物受体珠的纯化CRMP2-His蛋白与结合至谷胱甘肽包被供体珠的Ubc9-GST蛋白一起孵育。当受体珠与供体珠接近时,受体珠发射520-620nm之间的荧光信号。供体珠包含光敏剂,酞菁将环境氧转化为激发的单线态形式的氧。该单线态氧与受体珠上的二甲基噻吩衍生物反应,最终发生化学发光反应。只有珠彼此在约200纳米之内时才会发生该反应。单线态氧反应的强度还与存在的分析物的量成正比,并因此可用于筛选。使用这种基于珠的均相光激化学发光免疫分析(Amplified Luminescent Proximity HomogeneousAssay,ALPHA)技术(Perkin Elmer),检测了CRMP2-His和Ubc9-GST之间假定的相互作用。发现Ubc9通过亚微摩尔的亲和力与CRMP2结合;这种结合在至少18小时期间是稳定的。
可用于产生本发明化合物的一些方法显示如下:
如上所见,通常使用适当的芳香族化合物(即化合物的左部)作为起始材料,并将所需部分连接并转化为化合物的期望的右部。通过使用不同的“左部”以及不同的“右部”,可以制备多种本发明的化合物。还可以在中间体和/或产物中进行取代基的进一步转化以产生具有不同取代基的化合物。本发明化合物的具体实例包括但不限于以下化合物:
化合物AZ002的一些PK资料为:tmax=2hr,Cmax=263.1ng/ml,AUC(0-24hr)=2375.1hr.ng/ml,t1/2=5.8hr,生物可用性(F)=31%。在一些情况下,本发明的化合物作为药学上可接受的盐提供。适合的药学上可接受的盐包括本文公开的那些。在一些实施方式中,本发明的化合物的药学上可接受的盐提供更好的药代动力学。例如,化合物AZ002盐酸盐的药代动力学(“PK”)分析显示其比化合物AZ002本身具有更大的溶解度,抑制NaV1.7电流约45%而不影响其它CRMP2介导的功能。
图1至图5中示出了一些显示有效的化合物的生物学数据。简而言之,图1是示出了本发明的代表性化合物对培养的大鼠背根神经节(DRG)神经元中藜芦碱诱导胞质Na+增加的减弱能力的数据。这表明化合物能够通过与疼痛相关的电压门控Nav.17通道减少钠内流。DRG神经元负载Fura2-AM(一种Ca2+-敏感染料),然后用30μM藜芦碱处理以单独打开Na+通道(DMSO)或用5μM AZ化合物处理。通过计算应用藜芦碱和AZ化合物后120秒的曲线下面积(AUC)来定量藜芦碱诱导的细胞内钠浓度([Na+]c)随时间的变化。显示的数据是平均值±SEM。N=4个独立实验(每个实验n=104-520个细胞)。
图2A至图4D示出了化合物AZ002、AZ155和AZ191对原代大鼠DRG中河豚毒素敏感的(TTX-S)NaV1.7电流的影响。激活总结分别显示在图2A、图3A和图4A中。失活拟合总结分别显示在图2B、图3B和图4B中。图2C、图3C和图4C分别显示了化合物AZ002、AZ155和AZ191的电流-电压关系。图2D、图3D和图4D分别显示了用DMSO或化合物Az002、AZ155或AZ191处理的大鼠DRG的使用依赖性失活。数据是平均值±SEM。如示,N=10至11个细胞。
图5示出了化合物AZ002抑制大鼠和人DRG中TTX-S NaV1.7电流。子图A示出了对照(DMSO)和化合物AZ002处理的DRG的钠电流迹线。子图B示出了用各种浓度的AZ002处理的DRG的总结峰值电流。子图C是激活和失活拟合的图。子图D是混合的神经胶质-DRG共培养中人DRG(黄色箭头)的照片。子图E是显示对照(DMSO处理的)或AZ002化合物处理的人DRG的H-无限减去的(即NaV1.7)电流的迹线族。*,P<0.05(学生的t-检验)。
药物组合物:本发明包括药物组合物,其包含至少一种本发明的化合物,或单独的异构体、异构体的外消旋或非外消旋混合物,或其药学上可接受的盐或溶剂,以及至少一种药学上可接受的载体,以及任选的其它治疗和/或预防组分。
一般而言,本发明化合物以治疗有效量通过任何可接受的用于发挥相似用途的药剂的给药模式给药。根据许多因素,诸如待治疗的疾病的严重程度、受试者的年龄和相对健康状况、所用化合物的效力、给药途径和形式、给药所针对的适应症以及有关医师的偏好和经验,适合的剂量范围通常为每日1-500mg、通常为每日1-100mg,并且经常为每日1-30mg。治疗这些疾病的本领域普通技术人员通常无需过度实验而依靠个人知识和本申请的公开内容就能够确定本发明的化合物的治疗有效量。
通常地,本发明的化合物作为药物制剂被给药,药物制剂包括那些适合于口服(包括口腔和舌下)、直肠、鼻腔、局部、肺部、阴道或肠胃外(包括肌内、动脉内、鞘内、皮下和静脉内)给药或以适于通过吸入或吹入给药的形式。典型的给药方式一般是使用方便的日剂量方案进行口服,其可以根据患病程度进行调整。
可将本发明的一种或多种化合物与一种或多种常规佐剂、载体或稀释剂一起置于药物组合物和单位剂量的形式中。药物组合物和单位剂型可以由常规比例的常规成分组成,含有或不含有额外的活性化合物或组分,并且单位剂型可以包含任何适合的有效量的活性成分,与预期采用的每日剂量范围相当。药物组合物可以采用固体,诸如片剂或填充胶囊剂、半固体、粉剂、缓释制剂;或液体,诸如口服使用的溶液剂、混悬剂、乳剂、酏剂或填充胶囊剂;或者以用于直肠或阴道给药的栓剂形式;或以用于肠胃外使用的无菌注射溶液的形式。每片剂含有约一(1)毫克活性成分或更广泛地约0.01至约一百(100)毫克的制剂是相应合适的代表性单位剂型。
本发明的化合物可以按各种各样的口服给药剂型配制。药物组合物和剂型可以包含本发明的一种或多种化合物或其药学上可接受的盐作为活性组分。药学上可接受的载体可以是固体或液体。固体形式配制剂包括粉剂、片剂、丸剂、胶囊剂、扁囊剂、栓剂和可分散颗粒剂。固体载体可以是也可以作为稀释剂、调味剂、增溶剂、润滑剂、悬浮剂、粘合剂、防腐剂、片剂崩解剂或包封材料的一种或多种物质。在粉剂中,载体一般是细分的固体,是与细分活性组分的混合物。在片剂中,一般将活性组分与具有必要粘合能力的载体以适合比例混合并压制成期望的形状和尺寸。粉剂和片剂优选包含约一(1)至约七十(70)%的活性化合物。适合的载体包括但不限于碳酸镁、硬脂酸镁、滑石、糖、乳糖、果胶、糊精、淀粉、明胶、西黄蓍胶、甲基纤维素、羧甲基纤维素钠、低熔点蜡、可可脂等。术语“配制剂”旨在包括活性化合物与作为载体的包封材料的制剂,提供其中活性组分(包含或不包含载体)被载体包围的胶囊,该载体与其相关。同样地,包括扁囊剂和锭剂。片剂、散剂、胶囊剂、丸剂、扁囊剂和锭剂可以是适合于口服给药的固体形式。
适合于口服给药的其它形式包括液体形式配制剂,包括乳剂、糖浆剂、酏剂、水溶液、水性悬浮剂,或固体形式配制剂,其旨在使用前不久被转化为液体形式配制剂。乳剂可以在溶液中制备,例如在丙二醇水溶液中制备,或者可以包含乳化剂,例如,诸如卵磷脂、失水山梨糖醇单油酸酯或阿拉伯胶。水溶液可以通过将活性组分溶于水中并添加适合的着色剂、调味剂、稳定剂和增稠剂来制备。水性悬浮剂可以通过将细分的活性组分分散在具有粘性材料(诸如天然或合成胶、树脂、甲基纤维素、羧甲基纤维素钠和其它熟知的悬浮剂)的水中来制备。固体形式配制剂包括溶液、混悬剂和乳剂,并且除活性组分外,还可包含着色剂、调味剂、稳定剂、缓冲剂、人造和天然甜味剂、分散剂、增稠剂、增溶剂等。
本发明的化合物还可以配制成胃肠外给药(例如通过注射,例如推注或持续输注)并且可以以单位剂量形式存在与安瓿中、载药注射器中、添加了防腐剂的小容量输注或多剂量容器中。组合物可以采取在油性或水性负载体(vehicle)中的悬浮液、溶液或乳液的形式,例如以聚乙二醇水溶液的溶液。油性或非水性载体、稀释剂、溶剂或负载体的实例包括丙二醇、聚乙二醇、植物油(例如橄榄油)和可注射的有机酯(例如油酸乙酯),并且可以包含配制剂,诸如防腐剂、润湿剂、乳化剂或悬浮剂、稳定剂和/或分散剂。可替代地,活性成分可以是粉末形式,其通过无菌固体的无菌分离或通过溶液冻干获得,用于在使用前与适合的负载体如无菌无热原水进行构建。
本发明的化合物可配制成用于局部给药至表皮的软膏剂、霜剂或洗剂、或作为透皮贴剂。例如,软膏剂和霜剂可以例如用水性或油性基质并添加适合的增稠剂和/或凝胶剂来配制。洗剂可以用水性或油性基质配制,并且一般而言,还包含一种或多种乳化剂、稳定剂、分散剂、悬浮剂、增稠剂或着色剂。适用于口腔局部给药的制剂包括在调味基质(通常为蔗糖和阿拉伯胶或西黄蓍胶)中包含活性剂的锭剂;在惰性基质(诸如明胶和甘油或蔗糖和阿拉伯胶)中包含活性成分的软锭剂;和在适合的液体载体中包含活性成分的漱口剂。
本发明的化合物可配制成栓剂给药。首先熔化低熔点蜡,诸如脂肪酸甘油酯或可可脂的混合物,并将活性组分均匀分散,例如,通过搅拌。然后将熔化的均匀混合物倒入合适尺寸的模具中,使其冷却并固化。
本发明的化合物也可以配制成用于阴道给药。阴道栓剂、棉塞、霜剂、凝胶剂、糊剂、泡沫剂或喷雾剂除了活性成分之外还包含本领域已知的合适的载体。
本发明的化合物可以配制成用于鼻腔给药。通过常规手段将溶液剂或悬浮剂直接施用于鼻腔,例如用滴管、吸管或喷雾器。制剂可以以单剂量或多剂量形式提供。在后者滴管或吸管的情况下,这可以通过对患者给药适当的预定体积的溶液剂或悬浮剂来实现。在喷雾的情况下,这可以例如通过计量的雾化喷雾泵来实现。
本发明的化合物可以配制成用于气雾剂给药,特别是呼吸道并包括鼻内给药。该化合物一般具有小粒径,例如约五(5)微米或更小。这种粒径可以通过本领域已知的方式获得,例如通过微粉化。活性成分提供于加压包装中,并配有适合的推进剂,诸如氯氟烃(CFC)(例如,二氯二氟甲烷、三氯氟甲烷或二氯四氟乙烷)或二氧化碳或其它适合的气体。气雾剂还可适当地包含表面活性剂诸如卵磷脂。药的剂量可通过计量阀控制。可替代地,活性成分可以以干粉形式提供,例如,在适合的粉末基质诸如乳糖、淀粉、淀粉衍生物诸如羟丙基甲基纤维素和聚乙烯吡咯烷(PVP)中化合物的粉末混合物。粉末载体通常在鼻腔中形成凝胶。粉末组合物可以以单位剂量形式存在,例如,以(例如明胶的)胶囊或药筒形式,或以泡罩包装的形式,粉末可以通过吸入器的方式从中给药。
当需要时,制剂可以用适用于缓释或控释给药活性成分的肠溶衣制备。例如,本发明的化合物可以配制成透皮或皮下药物递送装置。当化合物的缓释是必需的或期望的并且当患者对治疗方案的依从性至关重要时,这些递送系统是有利的。透皮递送系统中的化合物经常附着在皮肤粘合剂固体支持物上。感兴趣的化合物也可以与渗透促进剂例如氮酮(1-十二烷基氮杂环庚烷-2-酮)组合。通过手术或注射将缓释递送系统皮下植入皮下层。皮下植入物将化合物包封在脂溶性膜中,例如硅橡胶或生物可降解聚合物(例如聚乳酸)。
药物配制剂通常为单位剂型。在这种形式中,配制剂通常细分为包含适量活性组分的单位剂量。单位剂型可以是包装的配制剂,该包装包含离散量的配制剂,诸如包装的片剂、胶囊和小瓶或安瓿中的粉剂。此外,单位剂型可以是胶囊剂、片剂、扁囊剂或锭剂本身,或者它可以是适当数量的任何这些包装形式。
其它适合的药物载体和它们的制剂描述于Remington:The Science andPractice of Pharmacy 1995,EW Martin编辑,Mack Publishing Company,19th edition,Easton,Pa中。
当用于治疗时,治疗有效量的式(I)化合物以及其药学上可接受的盐可以以原始化学品给药,可以将活性成分作为药物组合物给药。因此,本公开另提供了药物组合物,其包含治疗有效量的式(I)化合物或其药学上可接受的盐或其前药,以及一种或多种药学上可接受的载体、稀释剂或赋形剂。当联用时,该术语是指引起治疗效果的活性成分的联合量,无论是联合给药、连续给药或同时给药。式(I)的化合物及其药学上可接受的盐如上所述。载体、稀释剂或赋形剂在与制剂的其它成分相容并且对其接受者无害的意义上必须是可接受的。根据本公开的另一方面,还提供了用于制备药物配制剂的工艺,其包括将式(I)的化合物或其药学上可接受的盐或其前药与一种或多种药学上可接受的载体、稀释剂或赋形剂混合。
当本公开的组合物包含本公开的化合物和一种或多种额外的治疗剂或预防剂的组合时,化合物和附加剂二者通常以约10%至150%之间的剂量水平存在,并且更典型地在单药治疗方案中通常给药的剂量约为10%至80%之间。
本领域技术人员在研究其以下实施例时,本发明的额外目的、优点和新颖特征将会变得显而易见,这些实施例不旨在限制。在这些实施例中,用现在时来描述建设性地还原为实践的程序,并且用过去时表达已经在实验室中已经进行的程序。
实施例
计算机建模(In Silico Modeling):进行化合物与人CRMP2计算机对接。简而言之,分析对接了53个化合物的人CRMP2结构。使用计算筛选来搜索结合至CRMP2的小分子。对接集中在CRMP2上的口袋,其容纳SUMO化基序内的K374残基。使用Glide评分和其它能量相关条件对得到的复合物进行排序。大多数化合物对接在CRMP2上的2个不同位点上。化合物对接到CRMP 1、4和5的晶体结构上的Glide评分用于鉴定先导化合物。
筛选测定:通过ALPHA测定进行Ubc9-CRMP2抑制剂的筛选。简而言之,在计算机建模中鉴定为先导化合物的100μM化合物用于测定Ubc9-CRMP2蛋白质相互作用的抑制百分比以进一步鉴定先导化合物。
藜芦碱诱导的筛选:藜芦碱是NaV失活的抑制剂,增加了Na+通道的开放,导致去极化,其导致电压门控钙通道的开放。通过比率计Fura2-AM测定来监测钙内流。在此,将感觉神经元与本发明的各种化合物一起孵育过夜,并测试它们影响藜芦碱诱导钙流入的能力。绘制总结对照(DMSO,0.03%)和化合物中平均340nm/380nm比率的条形图。获得来自于每个条件下>100个细胞的数据。显示高于阈值的化合物被认为可能代表活化剂,而低于阈值的化合物被鉴定为影响Nav1.7的CRMP2的SUMO化的潜在抑制剂。
大鼠行为疼痛测定:化合物AZ002逆转神经损伤诱导的慢性疼痛模型中的机械超敏反应。椎管内给药AZ002(5μg/10μL)明显逆转神经性疼痛的保留性神经损伤模型中的机械超敏反应。缩爪阈值损伤后7天明显降低,这在AZ002给药(n=6,*p<0.05)后30至240分钟时间明显逆转而非负载体对照(DMSO)。
另外,AZ002(5μg/10μL)和AZ008(5μg/10μL)的椎管内给药明显逆转神经性疼痛的保留性神经损伤模型中的机械超敏反应。缩爪阈值损伤后7天明显降低,这在AZ002给药(n=6,*p<0.05)后15、30、90和120分钟时间以及AZ008给药(n=6,*p<0.05)后90、120、150和210分钟时间明显逆转。数据使用单向ANOVA分析,接着使用邓尼特多重比较测试(Dunnett's Multiple Comparison Test),使用伤后基线作为对照。
培养和转染儿茶酚胺A分化的(CAD)和人胚肾293(HEK293)细胞系:使小鼠神经元衍生的CAD和人衍生的HEK293细胞生长在标准细胞培养条件下,37℃,5%CO2。所有培养基补充10%FBS(Hyclone)和来自10,000μg/ml储液的1%青霉素/硫酸链霉素。将CAD细胞维持在DMEM/F12培养基中,并将HEK293细胞维持在DMEM培养基中。表达各种NaV1.X亚型的HEK293细胞系得自Theodore R.Cummins博士(Indiana University School ofMedicine)。通过磷酸钙沉淀转染pTarget载体中的hNaV1.1、pcDNA3.1-mod载体中的rNaV1.3或hNaV1.7或pRcCMVII载体中的hNaV1.5,产生稳定表达NaV1.X亚型的HEK293细胞。使用500μg/ml遗传霉素(Cat#10131035,Thermo Fisher Scientific,Waltham,MA)来选择NaV1.X表达细胞。由于NaV1.7对总钠电流的贡献约80%,选择CAD细胞作为模型神经元细胞系。这种约80%的贡献由HWTX-IV(Alomone Laboratories,Jerusalem,Israel)和ProTox-II(Sigma,St.Louis,MO)二者的亚型特异性NaV1.7阻断来确定。使用与2μg/μl CRMP2质粒和/或1μg/μl其它指示的质粒复合的1μg/μl聚乙烯亚胺(PEI)(Sigma,St.Louis,MO)转染细胞。在这些条件下,转染效率为约50%。为了获得蛋白质定量所需的更高转染效率,按照制造商的说明书对用Lipofectamine 2000(Cat#11668019,Thermo Fisher Scientific,Waltham,MA)转染的细胞进行若干蛋白质印迹(Western blot)。在这些情况下,转染效率通常>95%。按照制造商的说明书使用Lipofectamine 2000以500nM的浓度转染siRNA。转染后48h和72h之间进行所有实验。通过dsRed荧光验证质粒转染,并通过蛋白质印迹验证敲减。
大鼠原代背根神经节(DRG)神经元的培养和转染:从150-174g斯普拉-道来氏(Sprague-Dawley)大鼠中分离大鼠DRG神经元,然后使用已知程序转染。简而言之,去除背侧皮肤和肌肉并切割椎骨突起并行于解剖阶段暴露的DRG。然后收集DRG,在其根部修剪,并在包含中性蛋白酶(3.125mg.ml-1,Cat#LS02104,Worthington,Lakewood,NJ)和I型胶原酶(5mg.ml-1,Cat#LS004194,Worthington,Lakewood,NJ)的3ml无碳酸氢盐、无血清的无菌DMEM(Cat#11965,Thermo Fisher Scientific,Waltham,MA)中消化,并在37℃下温和搅拌中孵育45min。然后温和地离心离解的DRG神经元(~1.5×106)以收集细胞并用包含来自10,000μg/ml储液的1%青霉素/链霉素硫酸盐、30ng/ml神经生长因子和10%胎牛血清(Hyclone)的DRG培养基洗涤。将收集的细胞重悬于Nucleofector转染试剂中,Nucleofector转染试剂中包含上述使用浓度(working concentration)的质粒或siRNA。然后,将细胞在Amaxa Biosystem(Lonza,Basel,Switzerland)中进行电穿孔流程O-003,并铺板到聚-D-赖氨酸-和层粘连蛋白-涂覆的玻璃12-或15-mm盖玻片上。转染效率通常在20%至30%之间,约~10%细胞死亡。选择小直径神经元以靶向Aδ-和c-纤维伤害性神经元。对于大鼠DRG培养,小细胞被认为是~<30μm。
膜片钳电生理学:使用EPC 10放大器-HEKA在室温下进行全细胞电压钳和电流钳记录。用于电压钳CAD细胞记录的内部溶液包含(以mM计):110CsCl、5MgSO4、10EGTA、4ATPNa2-ATP和25HEPES(pH 7.3,290-310mOsm/L),并且外部溶液包含(以mM计):100NaCl、10四乙基氯化铵、1CaCl2、1CdCl2、1MgCl2、10D-葡萄糖、4 4-氨基吡啶、0.1NiCl2、10HEPES(pH7.3,310-315mosM/L)。对于DRG和HEK293细胞,用于电压钳记录的内部溶液包含(以mM计):140CsF、1.1Cs-EGTA、10NaCl和15HEPES(pH7.3,290-310mOsm/L),并且外部溶液包含(以mM计):140NaCl、3KCl、30四乙基氯化铵、1CaCl2、0.5CdCl2、1MgCl2、10D-葡萄糖、10HEPES(pH 7.3,310-315mosM/L)。对于DRG,用于电流钳的内部溶液包含(以mM计):140KCl、10NaCl、1MgCl2、1EGTA、10HEPES(pH7.2)和1ATP-Mg(pH 7.3,285-295mOsm/L),并且外部溶液包含(以mM计):154NaCl、5.6KCl、2CaCl2、2.0MgCl2、1.0葡萄糖和10HEPES(pH 7.4,305-315mOsm/L)。在用20μM Pitstop2(Cat#ab120687,Abcam,Cambridge,MA)阻止网格蛋白介导内吞作用的实验中,在实验前将化合物在组织培养孔中孵育30分钟。使用来自SutterInstruments的P-97电极拉制器从Warner Instruments的标准壁硼硅酸盐玻璃毛细管中拉出电极,并在充满内部溶液时加热抛光至最终电阻为1.5-3兆欧姆。全细胞电容和串联电阻通过线性泄漏电流进行补偿,通过电压钳实验的P/4方法和电流钳实验中补偿的电桥平衡进行数字减法。信号以10kHz过滤并在10-20kHz数字化。数据集中省略了其中串联电阻或电桥平衡超过15兆欧姆或在实验过程中波动超过30%的细胞。使用来自HEKA的Fitmaster软件和来自OriginLab Corp.的Origin9.0软件进行分析。
电压钳流程:使CAD和HEK293细胞经受电流密度(I-V)和快速失活电压流程。在I-V流程中,细胞在以5mV增量从-70mV至+60mV的20ms电压阶跃去极化之前保持在-80mV的钳制电位。这允许收集电流密度数据以分析钠通道的激活随电流与电压的变化以及峰电流密度,该峰电流密度通常在约0-10mV附近观察到并且归一化为细胞电容(pF)。在快速失活流程中,细胞在超极化之前保持在-80mV的钳制电位,并在-120mV至-10mV之间以5mV增量复极脉冲500ms。该步骤将各种百分比的通道调节为快速失活状态,使得20ms的0mV测试脉冲相对于归一化至最大电流可以显示相对较快的失活。使来自大鼠和人二者的DRG经受电流密度(I-V)流程和H-无限(前脉冲失活流程)。为了估计TTX-R贡献,在与500nM TTX孵育后运行I-V流程。保持在-100mV之后,以5mV增量从-70mV到+60mV的200ms电压阶跃允许分析峰值电流。TTX-R峰值电流密度始终在接近0mV的去极化和电压阶跃流程的10ms内测量。鉴于以前确定的NaV1.8和NaV1.9TTX-R电流的性质,该电压依赖性和活化曲线表明分析NaV1.8附近电流的峰值电流密度。因此,在电压脉冲至-60mV之后分析了150ms时存在的钠电流(已建立隔离Nav1.9电流的方法)。然而,在用CRMP2质粒电穿孔的细胞中,该流程没有观察到Nav1.9电流。可能的是,分析响应于CRMP2修饰改变的NaV1.9电流可能需要优化记录溶液和转染流程。不应从此TTX-R电流密度数据作出推论。
在H-无限流程中,细胞保持在-100mV,并使细胞经受调节电压阶跃1s,以10mV的增量从-120mV变化到0mV。该调节步骤之后是0mV的测试脉冲200ms以分析电流。H-无限流程允许从总电流(-120mV前脉冲之后可获得的电流)减去电隔离的TTX-R(-40mV前脉冲之后可获得的电流)以估算TTX-S电流。该流程是可能的,由于TTX-R与TTX-S通道的失活动力学不同,其中TTX-S电流被激活并在1s-40mV脉冲期间快速失活。对于所有流程,在电压流程之前和之后执行测试脉冲以评估电压流程期间的电流的下降或抬高并且省略来自细胞的电流随时间变化的数据。
鞘内留置导管:将大鼠麻醉(氯胺酮/甲苯噻嗪麻醉,80/12mg/kg腹腔注射;Sigma-Aldrich)并置于立体定位头部固定器中。将小脑延髓池暴露并切开,并植入8-cm导管(PE-10;Stoelting)终止于脊髓的腰部区域。将导管缝合(3-0丝线缝合)至深层肌肉中并在颈部后部外化;用自动缝合封闭皮肤。在留置套管植入后5-7天的恢复期之后,诱发保留性神经损伤。
保留性神经损伤(SNI):在异氟烷麻醉下(5%诱导,2L/min空气中维持2.0%),切开左后肢外侧面皮肤。直接解剖股二头肌以暴露坐骨神经的三个末端分支。简而言之,将腓总神经和胫骨分支用4-0丝线紧密结扎,并在结扎远端2.0mm处切断。假手术动物(Shamanimal)接受同样的手术;然而暴露的神经没有被结扎。切口的封闭分两层进行。肌肉用5-0可吸收缝线缝合一次;皮肤用自动缝合。在任何测试之前允许动物恢复5-7天。
机械性异常性疼痛:在行为评估之前,允许大鼠在悬吊的金属网笼内适应30分钟。在SNI之前(基线前)、在SNI之后(基线后)和最多达5小时之后用于测量对校准的冯弗雷细丝(von Frey filaments)(g)的反应,探测垂直于左后爪的外侧足底表面(上-下方法)。缩爪阈值使用Dixon非参数检验以克为单位计算,并表示为GraphPad Prism 6.0中的缩爪阈值(平均值±标准误差;SEM)。所有的行为实验都是盲法的。
化合物的合成:使用以下缩写:1-羟基苯并三唑(HOBt);二氯甲烷(DCM);乙酸乙酯(EtOAc);甲醇(MeOH);2-(1H-苯并三唑-1-基)-1,1,3,3-四甲基脲六氟磷酸盐(HBTU);N,N-二异丙基乙胺(DIPEA);N,N-二甲基甲酰胺(DMF);乙醇(EtOH);三乙胺(Et3N);薄层色谱(TLC);核磁共振(NMR);1-乙基-3-(3-二甲基氨基丙基)碳二亚胺(EDC)和1-[双(二甲基氨基)亚甲基]-1H-1,2,3-三唑并[4,5-b]吡啶鎓3-氧化六氟磷酸盐(HATU)。
一般过程:所有化学品均购自商业供应商。所有溶剂都从Fischer Scientific获得。使用硅胶(230/400目,Fisher Scientific)进行快速色谱。所有无水反应均在氮气正压下进行。在具有Zorbax C18反相柱的Agilent1100系列仪器上进行HPLC-MS分析。HRMS结果是在apex-Qe仪器上获得的。使用氘化溶剂在BRUKER AVANCE-III 400MHz NMR仪器上记录所有1H-NMR和13C-NMR谱。光谱以ppm表示并参考氘化DMSO(1H为2.49ppm,13C为39.5ppm)或氘化氯仿(1H为7.26ppm,13C为77ppm)。在Bruker 9.4T Apex-Qh FTICR质谱仪上获得高分辨率质谱(HRMS)。使用MS或UV吸光度检测器通过HPLC分析所有化合物的纯度。所有最终化合物都显示出≥95%的纯度。
3-氟-4-羟基-N-(4-(4-甲基哌嗪-1-基)苯基)苯甲酰胺的合成:在配有氮气入口和磁力搅拌棒的25-mL圆底烧瓶中,加入200mg(1.28mmol)3-氟-4-羟基苯甲酸。将亚硫酰氯(2ml,27.32mmol)缓慢加入到反应中。然后将混合物在110℃下搅拌2h,然后另加入亚硫酰氯(1ml,13.66mmol)。将反应混合物回流搅拌过夜。将过量的亚硫酰氯与甲苯共蒸发,得到225mg(100%)所需产物。粗产物用于下一步。将CH2Cl2(5mL)中的4-(4-甲基哌嗪-1-基)苯胺(245mg,1.28mmol)和Et3N(131mg,1.29mmol)加入到包含225mg(1.28mmol)3-氟-4-羟基苯甲酰氯的烧瓶中。然后将混合物在室温下搅拌过夜。向反应混合物中加入10mL水并过滤生成的绿色沉淀。将沉淀真空干燥,得到253mg(60%)所需产物,为深绿色固体。1H NMR(400MHz,氯仿-d)δ8.36(s,1H),7.64(s,1H),7.09(d,J=8.5Hz,1H),6.62(d,J=8.5Hz,2H),5.20(s,2H),4.32(bs,4H),2.54(t,J=5.1Hz,4H),2.34(d,J=0.7Hz,3H)。HPLC-MS:预期:330(MH+);实测:330。
3-氟-N-(4-(4-甲基哌嗪-1-基)苯基)-4-(2-(哌啶-1-基)乙氧基)苯甲酰胺的合 成:在配有氮气入口和磁力搅拌棒的圆底烧瓶中,碳酸钾(254mg,1.84mmol)、3-氟-4-羟基-N-(4-(4-甲基哌嗪-1-基)苯基)苯甲酰胺3(200mg,0.62mmol)、碘化钾(10mg,0.06mmol)和乙腈(5mL)。将混合物搅拌30分钟,然后加入4-(2-氯乙基)-哌啶盐酸盐(112mg,0.61mmol)。然后将混合物在回流温度下搅拌过夜。过滤形成的灰色沉淀,用水洗涤,然后真空干燥。HPLC显示反应中仍存在10%的3-氟-4-羟基-N-(4-(4-甲基哌嗪-1-基)苯基)苯甲酰胺。向反应中加入碳酸钾(38.10mg,0.28mmol)、碘化钾(1.5mg,0.006mmol)、乙腈(5mL)和4-(2-氯乙基)哌啶盐酸盐(16.8mg,0.09mmol)。然后将混合物在回流温度下搅拌过夜。过滤形成的灰色沉淀,用水洗涤,然后真空干燥,得到151mg(55%)的产物。使用极性反相HPLC纯化灰色固体,得到51mg(6%)的纯3-氟-N-(4-(4-甲基哌嗪-1-基)苯基)-4-(2-(哌啶-1-基)乙氧基)苯甲酰胺,为甲酸盐。1H NMR(400MHz,DMSO-d6)δ9.55(s,1H,NH+),8.51(s,1H,HCOO-),7.61(d,J=9.1Hz,2H),7.50(dd,J=13.5,2.3Hz,1H),7.45(dd,J=8.6,2.3Hz,1H),6.93(d,J=9.2Hz,2H),6.55(t,J=8.6Hz,1H),3.71-3.31(m,10H),3.16(s,3H),2.67(t,J=5.9Hz,2H),2.44-2.32(m,4H),1.53-1.40(m,4H),1.41-1.26(m,2H)。13C NMR(101MHz,DMSO-d6)δ165.58,164.95,145.33,133.46,125.42,121.46,119.14,116.27,114.78(d,J=21.2Hz),59.89,59.17,54.21,51.81,46.82,42.81,25.91,24.24。HPLC-MS:预期:441(MH+);实测:441。
4-羟基-3-甲氧基苯甲酸乙酯的合成:在配有氮气入口和磁力搅拌棒的圆底烧瓶中,加入香草酸(10g,59.49mmol)的EtOH(400mL)溶液。向上述溶液中加入600mg(6.11mmol)浓H2SO4。然后将混合物在回流温度下搅拌48h。旋转蒸发该溶液。然后将水(100mL)加入到残余物中,然后通过使用分液漏斗移除分离的绿色油。然后将产物真空干燥,得到11.45g(98%)4-羟基-3-甲氧基苯甲酸乙酯。1H NMR(400MHz,氯仿-d)δ7.62(dd,J=8.5,2.1Hz,1H),7.53(d,J=1.8Hz,1H),6.91(d,J=8.6Hz,1H),4.33(q,J=7.1Hz,2H),3.91(s,3H),1.36(t,J=7.3Hz,3H)。HPLC-MS:预期:197(MH+);实测:197。
3-甲氧基-4-((3-(三氟甲基)苄基)氧基)苯甲酸乙酯的合成:向配有氮气入口和磁力搅拌棒的圆底烧瓶中,加入碳酸钾(1.86g,13.46mmol)、4-羟基-3-甲氧基苯甲酸乙酯(1.2g,6.12mmol)和CH3CN(26mL)。将混合物搅拌30分钟,然后加入1-(溴甲基)-3-(三氟甲基)苯(1.59g,6.65mmol)。然后将混合物在回流温度下搅拌过夜。将反应混合物旋转蒸发。然后将水(100mL)加入到残余物中,然后将水相用EtOAc(3×50mL)萃取。将合并的有机层蒸发,然后真空干燥,得到2.08g(96%)的米色固体3-甲氧基-4-((3-(三氟甲基)苄基)氧基)苯甲酸乙酯。1H NMR(400MHz,氯仿-d)δ7.69(s,1H),7.63(d,J=2.0Hz,1H),7.60(d,J=2.0Hz,1H),7.57(d,J=2.0Hz,1H),7.56(s,1H),7.48(t,J=7.7Hz,1H),6.87(d,J=8.4Hz,1H),5.22(s,2H),4.34(q,J=7.1Hz,2H),3.93(s,3H),1.36(t,J=7.1Hz,3H)。HPLC-MS:预期:355(MH+);实测:355。
4-((4-氰苄基)氧基)-3-甲氧基苯甲酸乙酯的合成:使用类似于3-甲氧基-4-((3-(三氟甲基)苄基)氧基)苯甲酸乙酯的过程合成4-(4-氰苄基)氧基)-3-甲氧基苯甲酸乙酯,得到2.04g(49%)米色固体。1H NMR(400MHz,氯仿-d)δ7.80-7.35(m,6H),6.82(d,J=8.4Hz,1H),5.24(s,2H),4.34(q,J=7.1Hz,2H),3.93(s,3H),1.36(t,J=7.1Hz,3H)。
3-甲氧基-4-((4-(三氟甲氧基)苄基)氧基)苯甲酸乙酯的合成:使用类似于3-甲氧基-4-((3-(三氟甲基)苄基)氧基)苯甲酸乙酯的过程合成3-甲氧基-4-((4-(三氟甲氧基)苄基)氧基)苯甲酸乙酯,得到2.26g米色固体。1H NMR(400MHz,氯仿-d)δ7.61(ddd,J=8.4,2.0,0.8Hz,1H),7.56(s,1H),7.45(d,J=8.9Hz,2H),7.21(d,J=8.1Hz,2H),6.86(d,J=8.4Hz,1H),4.33(q,J=7.4Hz,1H),3.92(s,7H),1.36(t,J=7.1Hz,1H)。
3-甲氧基-4-((3-(三氟甲基)苄基)氧基)苯甲酸的合成:向配有氮气入口和磁力搅拌棒的圆底烧瓶中,加入3-甲氧基-4-((3-(三氟甲基)苄基)氧基)苯甲酸乙酯(2.08g,5.88mmol)的MeOH(28mL)溶液。向上述溶液中,加入8mL的5%NaOH溶液。将反应混合物在室温下搅拌过夜。将混合物旋转蒸发并加入20mL冷水。用6N HCl酸化水溶液。过滤沉淀,固体用5mL水洗涤,然后真空干燥,得到1.67g(87%)白色固体,为纯3-甲氧基-4-((3-(三氟甲基)苄基)氧基)苯甲酸。1H NMR(400MHz,甲醇-d4)δ7.77(s,1H),7.71(d,J=6.7Hz,1H),7.69-7.47(m,4H),7.07(dd,J=8.4,2.7Hz,1H),5.24(s,2H),3.88(s,3H)。
4-((4-氰苄基)氧基)-3-甲氧基苯甲酸的合成:使用类似于3-甲氧基-4-((3-(三氟甲基)-苄基)氧基)苯甲酸的过程合成4-((4-氰苄基)氧基)-3-甲氧基苯甲酸,得到1.28g(74%)的白色固体,为纯的所需产物。1H NMR(400MHz,氯仿-d)δ7.65(dt,J=6.3,1.4Hz,2H),7.61-7.56(m,1H),7.56-7.50(m,3H),7.24(t,J=1.7Hz,1H),5.22(s,2H),3.92(s,3H)。HPLC-MS(负离子模式):预期:282(M-1);实测:282。
3-甲氧基-4-((4-(三氟甲氧基)苄基)氧基)苯甲酸的合成:使用类似于3-甲氧基-4-((3-(三氟甲基)-苄基)氧基)苯甲酸的过程合成3-甲氧基-4-((4-(三氟甲氧基)苄基)氧基)苯甲酸,得到2.096g(100%)白色固体,为纯的和所需产物。1H NMR(400MHz,氯仿-d)δ7.58(dd,J=15.1,1.9Hz,2H),7.45(d,J=8.7Hz,2H),7.21(d,J=8.6Hz,2H),6.87(d,J=8.5Hz,1H),5.17(s,2H),3.87(s,3H)。HPLC-MS(负离子模式):预期:341(M-1);实测:341。
3-甲氧基-4-((3-(三氟甲基)苄基)氧基)苯甲酰氯的合成:在包含300mg(0.83mmol)3-甲氧基-4-((3-(三氟甲基)苄基)氧基)苯甲酸的25-mL圆底烧瓶中,加入亚硫酰氯(1.5ml,20.68mmol)。将混合物在110℃搅拌2h,然后另加入亚硫酰氯(1.0ml,13.78mmol)。将反应混合物回流搅拌过夜。将过量的亚硫酰氯与甲苯共蒸发,得到292mg(>100%)的3-甲氧基-4-((3-(三氟甲基)苄基)氧基)苯甲酰氯。该化合物用于下一步。
4-((4-氰苄基)氧基)-3-甲氧基苯甲酰氯的合成:使用类似于3-甲氧基-4-((3-(三氟甲基)苄基)氧基)苯甲酰氯的过程合成4-((4-氰苄基)氧基)-3-甲氧基苯甲酰氯,得到451mg(85%)所需产物,为米色固体。1H NMR(400MHz,氯仿-d)δ7.75(d,J=8.5Hz,1H),7.66(t,J=7.9Hz,2H),7.55(s,2H),7.53(s,1H),6.85(dd,J=22.7,8.6Hz,1H),5.26(s,2H),3.93(s,3H)。
3-甲氧基-4-((4-(三氟甲氧基)苄基)氧基)苯甲酰氯的合成:使用类似于3-甲氧基-4-((3-(三氟甲基)苄基)氧基)苯甲酰氯的过程合成3-甲氧基-4-((4-(三氟甲氧基)苄基)氧基)苯甲酰氯,463mg(78%)的所需产物,为米色固体。该化合物用于下一步。
3-甲氧基-N-(4-(4-甲基哌嗪-1-基)苯基)-4-((4-(三氟甲氧基)苄基)氧基)苯甲 酰胺的合成:在配有氮气入口和磁力搅拌棒的圆底烧瓶中,加入3-甲氧基-4-((4-(三氟甲氧基)苄基)氧基)苯甲酰氯(147mg,0.41mmol)、4-(4-甲基哌嗪-1-基)苯胺(78mg,0.41mmol)和Et3N(0.13mL,0.93mmol)的CH2Cl2(5mL)溶液。然后将混合物在室温下搅拌过夜。过滤混合物,用CH2Cl2洗涤浅灰色固体,然后真空干燥,得到17mg(8%)纯的3-甲氧基-N-(4-(4-甲基哌嗪-1-基)苯基)-4-((4-(三氟甲氧基)苄基)氧基)苯甲酰胺。1H NMR(400MHz,DMSO-d 6)δ9.88(s,1H),7.65-7.43(m,6H),7.38(d,J=8.2Hz,2H),7.11(d,J=8.6Hz,1H),6.88(d,J=9.0Hz,2H),5.18(s,2H),3.82(s,3H),3.16-2.89(m,4H),2.44-2.33(m,4H),2.18(s,3H)。13C NMR(101MHz,DMSO-d6)δ164.70,150.50,148.97,148.35,147.81,136.73,131.46,130.43,129.87,128.12,122.34,121.81(d,J=10.9Hz),121.29(d,J=14.4Hz),120.77,115.84,112.90(d,J=39.0Hz),111.66(d,J=59.9Hz),69.30,56.13(d,J=16.7Hz),55.07(t,J=30.8Hz),48.91,46.21(d,J=31.9Hz)。HPLC-MS:预期:516(MH+);实测:516。HPLC-MS:预期:516(MH+);实测:516。
3-甲氧基-N-(4-(4-甲基哌嗪-1-基)苯基)-4-((3-(三氟甲基)苄基)氧基)苯甲酰 胺的合成:在配有氮气入口和磁力搅拌棒的圆底烧瓶中,加入3-甲氧基-4-((3-(三氟甲基)苄基)氧基)苯甲酰氯(143mg,0.415mmol)、4-(4-甲基哌嗪-1-基)苯胺(79.4mg,0.415mmol)和Et3N(0.15mL,1.08mmol)的CH2Cl2(5mL)溶液。然后将混合物在室温下搅拌过夜。然后过滤粗产物,得到白色固体。将固体白色固体用CH2Cl2洗涤,真空干燥,得到10mg所需化合物。向滤液中加入10mL水并将水相用CH2Cl2萃取。有机层经Na2SO4干燥、过滤、旋转蒸发。通过用10%MeOH的CH2Cl2溶液的制备TLC纯化粗产物,得到80mg的3-甲氧基-N-(4-(4-甲基哌嗪-1-基)苯基)-4-((3-(三氟甲基)苄基)氧基)苯甲酰胺。总产量为90mg(39%)。1H NMR(400MHz,DMSO-d6)δ9.86(s,1H),7.82(s,1H),7.75(d,J=9.0Hz,1H),7.69(d,J=8.8Hz,1H),7.62(t,J=8.2Hz,1H),7.58-7.45(m,4H),7.14(d,J=8.6Hz,1H),6.89(d,J=9.1Hz,2H),5.26(s,2H),3.83(s,3H),3.15-2.95(m,4H),2.48(t,J=4.7Hz,4H,部分被DMSO NMR溶剂峰覆盖),2.21(s,3H)。13C NMR(101MHz,DMSO-d6)δ164.72,150.47,149.10,147.84,138.81,132.25,131.52,130.08,128.37,125.93-125.06(m),124.64(d,J=4.1Hz),122.07,121.10,115.92,113.17,111.76,69.50,56.20,55.05,48.88,46.12。HPLC-MS:预期:500(MH+);实测:500。
4-((4-氰苄基)氧基)-3-甲氧基-N-(4-(4-甲基哌嗪-1-基)苯基)苯甲酰胺的合 成:用类似于合成3-甲氧基-N-(4-(4-甲基哌嗪-1-基)苯基)-4-((3-(三氟甲基)苄基)氧基)苯甲酰胺的过程制备4-((4-氰苄基)氧基)-3-甲氧基-N-(4-(4-甲基哌嗪-1-基)苯基)苯甲酰胺。1H NMR(400MHz,DMSO-d6)δ9.96(s,1H),7.85(d,J=8.4Hz,2H),7.67-7.57(m,4H),7.57-7.50(m,2H),7.09(d,J=9.1Hz,2H),6.96(d,J=9.1Hz,2H),5.27(s,2H),3.84(s,3H),3.80-3.50(m,4H),2.75(s,3H),在2.58-2.28(bs,来自哌嗪环的4个质子被DMSO峰覆盖)。13C NMR(101MHz,DMSO-d6)δ165.02,150.30,148.98,146.32,142.94,132.86(d,J=32.3Hz),132.39,128.58(d,J=36.7Hz),128.06,122.23(d,J=37.8Hz),121.15(d,J=38.5Hz),119.20,116.67,113.03(d,J=15.9Hz),111.60(d,J=37.6Hz),110.92,69.27,56.16(d,J=22.9Hz),52.91,46.53,42.68(d,J=28.4Hz)。HPLC-MS:预期:457(MH+);实测:457。
4-((4-氰苄基)氧基)-3-甲氧基-N-(4-(4-甲氧基哌啶-1-基)苯基)苯甲酰胺的合 成:在配有氮气入口和磁力搅拌棒的圆底烧瓶中,加入4-(4-氰苄基)氧基)-3-甲氧基苯甲酰氯(142mg,0.47mmol)、4-(4-甲氧基哌啶-1-基)苯胺(97mg,0.47mmol)和Et3N(0.14mL,1.00mmol)的CH2Cl2(5mL)溶液。反应混合物用H2O洗涤,水相用CH2Cl2萃取。有机层用Na2SO4干燥、过滤,然后使用旋转蒸发器浓缩。向残余物中加入10mL CH2Cl2和4mL 3N甲醇的HCl,并在室温下搅拌5h。浓缩反应混合物,然后真空干燥,得到黑色固体为粗产物。将产物溶于EtOH中,过滤灰色化合物并真空干燥,得到50mg(21%)4-((4-氰苄基)氧基)-3-甲氧基-N-(4-(4-甲氧基哌啶-1-基)苯基)-苯甲酰胺(100%HPLC纯度)。1H NMR(400MHz,DMSO-d6)δ10.34(s,1H),7.92-7.82(m,4H),7.79-7.66(m,2H),7.62(d,J=6.7Hz,2H),7.60-7.55(m,3H),7.12(d,J=9.1Hz,1H),5.28(s,2H),3.85(s,3H),3.61-3.48(m,5H),3.27(s,3H),2.29-2.11(m,2H),2.08-1.88(m,2H)。13C NMR(101MHz,DMSO-d6)δ165.40,150.71,149.10,142.97,133.86-131.37(m),128.85,128.25,127.67,122.79-120.35(m),121.14,119.16,113.31,112.83,112.28,111.67,111.00,69.31,56.34,56.22,55.84,55.53。HPLC-MS:预期:472(MH+);实测:472。
N-(4-(4-甲氧基哌啶-1-基)苯基)苯并[d][1,3]二氧杂环戊烯-5-甲酰胺的合成:在配有氮气入口和磁力搅拌棒的圆底烧瓶中,加入苯并[d][1,3]二氧杂环戊烯-5-羰基氯(136mg,0.74mmol)、4-(4-甲氧基哌啶-1-基)苯胺(150mg,0.74mmol)和Et3N(0.30mL,2.15mmol)的CH2Cl2(5mL)溶液。然后将混合物在室温下搅拌过夜。向反应中加入20mL水并进行分层。然后用CH2Cl2(2×15mL)洗涤水层。然后将合并的有机溶剂用Na2SO4干燥、过滤,通过旋转蒸发浓缩,然后真空干燥。通过柱色谱法纯化粗产物,并用35%EtOAc的己烷溶液洗脱产物,得到41mg(16%)N-(4-(4-甲氧基哌啶-1-基)苯基)苯并[d][1,3]二氧杂环戊烯-5-甲酰胺,为米色固体。1H NMR(400MHz,CDCl3)δ7.54-7.50(m,3H),7.45(s,1H),7.00(d,J=8Hz,1H),6.88(d,J=8Hz,2H),6.09(s,2H),3.43-3.37(m,2H),3.30-3.25(m,1H),3.23(s,3H),2.82-2.76(m,2H),1.91-1.87(m,2H),1.52-1.44(m,2H)。13C NMR(101MHz,DMSO-d 6)δ164.30,150.20,147.80,147.73,131.25,129.36,122.99,121.89,116.35,108.30,108.00(d,J=4.5Hz),102.12(t,J=6.1Hz),75.83,55.26(d,J=4.3Hz),47.15,30.61。HPLC-MS:预期:355(MH+);实测:355。
N-(4-(4-甲基哌嗪-1-基)苯基)苯并[d][1,3]二氧杂环戊烯-5-甲酰胺的合成:在配有氮气入口和磁力搅拌棒的圆底烧瓶中,加入苯并[d][1,3]二氧杂环戊烯-5-羰基氯(164mg,0.89mmol)、4-(4-甲基哌嗪-1-基)苯胺(170mg,0.89mmol)和Et3N(0.38mL,2.73mmol)的CH2Cl2(5mL)溶液。然后将混合物在室温下搅拌过夜。然后过滤形成的沉淀,用CH2Cl2洗涤并将残余物真空干燥,得到205mg(68%)N-(4-(4-甲基哌嗪-1-基)苯基)苯并[d][1,3]二氧杂环戊烯-5-甲酰胺,为黑色固体。1H NMR(400MHz,CDCl3)δ9.83(s,1H,NH),7.55-7.52(m,3H),7.50(s,1H),7.00(d,J=8Hz,1H),6.87(d,J=8Hz,2H),6.09(s,2H),3.05(t,J=8Hz,4H),2.41(t,J=8Hz,4H),3.23(s,3H)。13C NMR(101MHz,DMSO-d6)δ164.30,150.20,147.83,147.73,131.45,129.35,12.03,121.87(d,J=4.5Hz),115.85,108.30,108.00(d,J=4.5Hz),102.15(t,J=6.1Hz),55.07,48.90,46.21(d,J=4.3Hz)。HPLC-MS:预期:340(MH+);实测:340。
3-氟-4-羟基苯甲酸乙酯的合成:用类似于制备4-羟基-3-甲氧基苯甲酸乙酯的过程合成3-氟-4-羟基苯甲酸乙酯,得到1.67g(56%)的黄色油状物的所需产物,该产物在储存时变成米黄色固体。1H NMR(400MHz,甲醇-d4)δ7.87-7.36(m,2H),7.94(t,J=7.6Hz,1H),4.30(q,J=7.4Hz,2H),1.34(t,J=7.1Hz,3H)。HPLC-MS:预期:185(MH+);实测:185
3-氟-4-(2-吗啉基乙氧基)苯甲酸乙酯的合成:用类似于制备3-甲氧基-4-((3-(三氟甲基)苄基)氧基)苯甲酸乙酯的过程合成3-氟-4-(2-吗啉基乙氧基)苯甲酸乙酯,得到1.26g(98%)米色固体的所需产物。1H NMR(400MHz,氯仿-d)δ7.77(d,J=8.5Hz,1H),7.72(d,J=11.7Hz,1H),6.95(t,J=9.1Hz,1H),4.32(q,J=7.6Hz,2H),4.21(t,J=5.7Hz,2H),3.74-3.66(m,4H),2.83(t,J=5.7Hz,2H),2.63-2.45(m,4H),1.35(t,J=7.1Hz,3H)。HPLC-MS:预期:299(M+1);实测:299。
3-氟-4-(2-吗啉基乙氧基)苯甲酸的合成:用类似于制备3-甲氧基-4-((3-(三氟甲基)苄基)氧基)苯甲酸的过程合成3-氟-4-(2-吗啉基乙氧基)苯甲酸,得到1.25g(100%)米色固体,为纯的所需产物。1H NMR(400MHz,甲醇-d4)δ8.51(s,1H),7.70(d,J=8.5Hz,1H),7.62(dd,J=12.4,2.0Hz,1H),7.06(t,J=8.4Hz,1H),4.23(t,J=5.4Hz,2H),3.70-3.64(m,2H),2.83(t,J=5.4Hz,2H),2.67-2.56(m,4H),2.51(t,J=6.0Hz,2H)。HPLC-MS:预期:270(MH+);实测:270。
3-氟-N-(4-(4-甲基哌嗪-1-基)苯基)-4-(2-吗啉基乙氧基)苯甲酰胺的合成:在配有磁力搅拌棒和氮气入口的圆底烧瓶中,加入3-氟-4-(2-吗啉基乙氧基)苯甲酸(135mg,0.05mmol)、HATU(494mg,1.3mmol)和DIPEA(0.1mL,0.73mmol)在3mL DMF中的混合物。然后将混合物在室温下搅拌一小时。向上述溶液中加入4-(4-甲基哌嗪-1-基)苯胺(95mg,0.50mmol)。将混合物在室温下搅拌16h。将饱和NaHCO3水溶液加入混合物并用CH2Cl2萃取水相。将合并的有机层用Na2SO4干燥、过滤、通过旋转蒸发移除,并通过用10%MeOH的DCM溶液制备TLC纯化粗产物,得到126mg(57%)纯3-氟-N-(4-(4-甲基哌嗪-1-基)苯基)-4-(2-吗啉基乙氧基)苯甲酰胺。1H NMR(400MHz,氯仿-d)δ7.62-7.54(m,2H),7.46(d,J=8.9Hz,2H),6.96(t,J=8.5Hz,1H)6.87(d,J=9.0Hz,2H),4.19(t,J=5.7Hz,2H),3.69(t,J=4.8Hz,4H),3.15(t,J=5.2Hz,4H),2.81(t,J=5.7Hz,2H),2.60-2.49(m,8H),2.32(s,3H)。13C NMR(101MHz,氯仿-d)δ163.98,153.32,150.86,149.57(d,J=10.9Hz),148.42,130.16,128.08(d,J=5.5Hz),123.50(d,J=15.5Hz),121.78(d,J=14.4Hz),116.49,115.37,114.10,67.55(t,J=7.3Hz),66.90(t,J=15.2Hz),57.30(t,J=8.6Hz),55.04(t,J=11.8Hz),54.11(t,J=12.9Hz),49.36(t,J=3.6Hz),46.11(d,J=14.2Hz)。HPLC-MS:预期:443(MH+);实测:443。
前述本发明的讨论是为了说明和描述的目的而提出的。前述内容并非旨在将本发明限制于本文所公开的一种或多种形式。虽然本发明的描述已经包括对一种或多种实施实施方式以及某些变型和修改的描述,但是在理解本公开内容之后,其它变型和修改也在本发明的范围内,例如可能在本领域技术人员的技能和知识范围内。旨在获得包括在允许的程度内的替代实施方式的权利,包括与要求保护那些相对应的替代的、可互换的和/或等同的结构、功能、范围或步骤,不管这种替代的、可互换的和/或等同的结构、功能、范围或步骤是否在本文中公开,并且无意公开奉献任何可专利主题。本文引用的所有参考文献,其全部内容通过引用并入本文。
Claims (8)
3.如权利要求1或2所述的化合物在制备用于抑制受试者中CRMP2的SUMO化的试剂中的用途,其中所述试剂通过在CRMP2结合口袋中对接用于治疗状况,所述CRMP2结合口袋的特征在于以下CRMP2氨基酸残基的一种或多种:LYS23、MET64、SER322、TRP366、VAL370、VAL371、GLY373、LYS374、MET375、GLU377、GLN379、PRO414和ARG440,所述状况是疼痛。
4.根据权利要求3所述的用途,其中,所述CRMP2结合口袋的特征在于以下CRMP2氨基酸残基:LYS23、MET64、SER322、TRP366、VAL370、VAL371、GLY373、LYS374、MET375、GLU377、GLN379、PRO414和ARG440。
5.根据权利要求3或4所述的用途,其中,所述试剂是具有取代的甲基-哌嗪-苯基-苯甲酰胺核心的小分子化合物。
7.根据权利要求3-6中任一项所述的用途,其中,所述受试者是人类患者。
8.根据权利要求7所述的用途,其中,所述人类患者患有与Nav1.7活性相关的疼痛。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201562238182P | 2015-10-07 | 2015-10-07 | |
US62/238,182 | 2015-10-07 | ||
PCT/US2016/056051 WO2017062804A1 (en) | 2015-10-07 | 2016-10-07 | Crmp2 sumoylation inhibitors and uses thereof |
Publications (2)
Publication Number | Publication Date |
---|---|
CN108289882A CN108289882A (zh) | 2018-07-17 |
CN108289882B true CN108289882B (zh) | 2020-12-29 |
Family
ID=58488606
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201680068806.1A Active CN108289882B (zh) | 2015-10-07 | 2016-10-07 | Crmp2 sumo化抑制剂以及其用途 |
Country Status (9)
Country | Link |
---|---|
US (2) | US10441586B2 (zh) |
EP (1) | EP3359151A4 (zh) |
JP (1) | JP6934196B2 (zh) |
CN (1) | CN108289882B (zh) |
AU (2) | AU2016334102B2 (zh) |
CA (2) | CA3090492C (zh) |
MX (1) | MX2018004164A (zh) |
NZ (1) | NZ742038A (zh) |
WO (1) | WO2017062804A1 (zh) |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP6934196B2 (ja) * | 2015-10-07 | 2021-09-15 | アリゾナ ボード オブ リージェンツ オン ビハーフ オブ ザ ユニバーシティ オブ アリゾナ | Crmp2のsumo付加抑制剤 |
WO2018144900A1 (en) * | 2017-02-03 | 2018-08-09 | Arizona Board Of Regents On Behalf Of The University Of Arizona | Small molecule antagonists of sumo related modification of crmp2 and uses thereof |
WO2022226133A1 (en) * | 2021-04-21 | 2022-10-27 | University Of Florida Research Foundation, Incorporated | Multifaceted approach to novel interleukin-6 inhibitors |
Family Cites Families (14)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2870146A (en) | 1958-02-10 | 1959-01-20 | Bristol Lab Inc | Therapeutic agents |
IT1126509B (it) | 1979-12-07 | 1986-05-21 | Medea Res Srl | Benzimidi ad attivita' anestetica locale e antiaritmica,processo per la loro preparazione e composizioni farmaceutiche che le contengono |
US7037927B2 (en) | 2003-10-16 | 2006-05-02 | Abbott Laboratories | Amides that inhibit vanilloid receptor subtype 1 (VR1) receptor |
CN101855210A (zh) * | 2007-10-11 | 2010-10-06 | 沃泰克斯药物股份有限公司 | 用作电压-门控钠通道抑制剂的酰胺类 |
NZ584519A (en) | 2007-10-11 | 2012-07-27 | Vertex Pharma | Aryl amides useful as inhibitors of voltage-gated sodium channels |
WO2009086303A2 (en) * | 2007-12-21 | 2009-07-09 | University Of Rochester | Method for altering the lifespan of eukaryotic organisms |
WO2011051350A1 (en) | 2009-10-27 | 2011-05-05 | Ucb Pharma S.A. | Function modifying nav 1.7 antibodies |
US8319136B2 (en) | 2010-06-29 | 2012-11-27 | Schneider Electric USA, Inc. | Arcing fault and arc flash protection system having a high-speed switch |
WO2012027392A2 (en) | 2010-08-24 | 2012-03-01 | Brigham Young University | Antimetastatic compounds |
BR112013009365B1 (pt) | 2010-10-18 | 2021-10-26 | Raqualia Pharma Inc | Composto e seu uso, composição farmacêutica e processo para preparar uma composição farmacêutica |
ES2687481T3 (es) | 2013-03-15 | 2018-10-25 | Chromocell Corporation | Moduladores del canal de sodio para el tratamiento del dolor |
SG11201606367YA (en) | 2014-02-06 | 2016-09-29 | Abbvie Inc | 6-heteroaryloxy- and 6-aryloxy-quinoline-2-carboxamides and uses thereof |
EP3119415A4 (en) | 2014-03-07 | 2017-11-29 | The Arizona Board of Regents on behalf of the University of Arizona | Non-narcotic crmp2 peptides targeting sodium channels for chronic pain |
JP6934196B2 (ja) * | 2015-10-07 | 2021-09-15 | アリゾナ ボード オブ リージェンツ オン ビハーフ オブ ザ ユニバーシティ オブ アリゾナ | Crmp2のsumo付加抑制剤 |
-
2016
- 2016-10-07 JP JP2018517688A patent/JP6934196B2/ja active Active
- 2016-10-07 EP EP16854447.6A patent/EP3359151A4/en not_active Withdrawn
- 2016-10-07 MX MX2018004164A patent/MX2018004164A/es unknown
- 2016-10-07 NZ NZ742038A patent/NZ742038A/en unknown
- 2016-10-07 CN CN201680068806.1A patent/CN108289882B/zh active Active
- 2016-10-07 CA CA3090492A patent/CA3090492C/en active Active
- 2016-10-07 CA CA3001075A patent/CA3001075C/en active Active
- 2016-10-07 AU AU2016334102A patent/AU2016334102B2/en active Active
- 2016-10-07 US US15/766,299 patent/US10441586B2/en active Active
- 2016-10-07 WO PCT/US2016/056051 patent/WO2017062804A1/en active Application Filing
-
2019
- 2019-10-08 US US16/596,508 patent/US11020391B2/en active Active
-
2020
- 2020-01-31 AU AU2020200720A patent/AU2020200720A1/en not_active Abandoned
Also Published As
Publication number | Publication date |
---|---|
AU2016334102B2 (en) | 2019-10-31 |
MX2018004164A (es) | 2018-08-01 |
AU2016334102A8 (en) | 2018-05-24 |
CN108289882A (zh) | 2018-07-17 |
AU2016334102A1 (en) | 2018-05-17 |
JP2018529748A (ja) | 2018-10-11 |
CA3001075C (en) | 2020-10-27 |
US20200093822A1 (en) | 2020-03-26 |
CA3001075A1 (en) | 2017-04-13 |
NZ742038A (en) | 2019-08-30 |
WO2017062804A1 (en) | 2017-04-13 |
JP6934196B2 (ja) | 2021-09-15 |
EP3359151A1 (en) | 2018-08-15 |
US11020391B2 (en) | 2021-06-01 |
EP3359151A4 (en) | 2019-08-14 |
AU2020200720A1 (en) | 2020-02-20 |
US20180289700A1 (en) | 2018-10-11 |
CA3090492C (en) | 2023-02-14 |
CA3090492A1 (en) | 2017-04-13 |
US10441586B2 (en) | 2019-10-15 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
AU2018282747B2 (en) | Compounds for modulating S1P1 activity and methods of using the same | |
EP3009427B1 (en) | Benzimidazole inhibitors of the sodium channel | |
JP5203712B2 (ja) | 選択的アンドロゲン受容体モジュレータとしてのアミノフェニル誘導体 | |
US11020391B2 (en) | CRMP2 sumoylation inhibitors and uses thereof | |
WO2009132454A1 (en) | Di-t-butylphenyl piperazines as calcium channel blockers | |
WO2009146540A1 (en) | N-piperidinyl acetamide derivatives as calcium channel blockers | |
CA2722704A1 (en) | Cyclylamine derivatives as calcium channel blockers | |
EP2119704A1 (en) | Acylguanidine derivative | |
US20170065602A1 (en) | Compounds with trpv4 activity, compositions and associated methods thereof | |
WO2014134306A1 (en) | Heterocyclic inhibitors of the sodium channel | |
CN111825611A (zh) | 4(1h)-奎诺酮衍生物及其用途 | |
WO2009123080A1 (ja) | インドリノン化合物 | |
US9458102B2 (en) | Derivatives of tetracaine | |
US20090270338A1 (en) | Diaryl-cyclylalkyl derivatives as calcium channel blockers | |
WO2021083246A1 (zh) | 四元环类衍生物调节剂、其制备方法和应用 | |
CA2940897A1 (en) | Heterocyclic inhibitors of the sodium channel | |
CA2583302A1 (en) | Novel oxadiazinone derivatives and use thereof as ppar-alpha modulators |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant |